THE INSIDER S GUIDE TO METASTATIC BREAST CANCER A Summary f the Disease and its Treatments by Anne Leser DISCLAIMER The material herein has been gleaned frm bks, Internet surces and ther metastatic breast cancer (MBC) patients. It is nt a substitute fr prfessinal medical diagnsis, treatment, r directin. The authr, a metastatic breast cancer patient, is a laypersn with n medical training. She des nt advcate any specific treatment(s) r type(s) f therapies listed herein. The authr des nt, and will nt, accept respnsibility r liability fr any decisins, actins, r treatments undertaken by the reader as the result f reading this dcument. All readers are instructed t discuss any ptentially new therapy r remedy with their medical team befre taking actin. THE VIEWER MUST AGREE TO RENDER THE AUTHOR BLAMELESS FOR ANY AND ALL ACTIONS TAKEN BY THE VIEWER AS THE RESULT OF READING THIS DOCUMENT. IF THE TERMS OF THIS DISCLAIMER ARE UNACCEPTABLE TO THE VIEWER, THEN THE VIEWER MUST NEITHER OPEN NOR DOWNLOAD THIS DOCUMENT.
TABLE OF CONTENTS Dedicatin... 3 Abut the Authr... 3 Overview and Suggestins... 3 Helpful Hints and Facts... 4 Types f Breast Cancer and Related Tests... 7 Hrmne Psitive Breast Cancer, Hrmnal Therapies, and Hrmnal Therapy Resistance... 12 HER2 Psitive Breast Cancer and Related Therapies... 19 Triple Negative Breast Cancer and Related Therapies... 22 Triple Psitive Breast Cancer and Related Therapies... 24 Male Breast Cancer... 25 Tests fr Breast Cancer Spread (Metastasis)... 27 Oligmetastasis... 30 Cnditinal Survival... 31 The Micrenvirnment... 31 Persnalized Medicine... 32 Free Prfessinal Secnd Opinin... 35 Bisimilars... 35 MBC Cnventinal Therapies Overview... 36 Chemtherapy... 36 Hrmnal Therapy... 44 Targeted Therapy... 48 Chemtherapy Resistance... 52 Clinical Trials Overview... 52 Access t Unapprved Medicatins... 56 Tumr Bipsy fr New Metastatic Sites... 57 Bne Metastasis... 59 Bne Marrw Metastasis... 62 Liver Metastasis... 62 Lung Metastasis... 66 Brain Metastasis... 68 Leptmeningeal (Spinal Fluid) Metastasis... 74 Abdminal, Peritneal, Omentum, and Ovarian Metastasis... 79 Cpyright 2015 Anne Leser Updated Oct. 2017 Page 1
Ocular Metastasis... 82 Skin (Cutaneus) Metastasis and Ulcerating Breast Tumrs... 82 Research and Ptentially Helpful Therapies... 84 Research and Ptential Therapies fr All Categries f Breast Cancer... 85 Research and Ptential Therapies fr Hrmne Receptr Psitive MBC... 93 Research and Ptential Therapies fr HER2 Psitive MBC... 99 Research and Ptential Therapies fr HER2 Negative MBC (Including TNBC)... 101 Research and Ptential Therapies Slely fr TNBC... 101 Research and Ptential Therapies Slely fr Patients with BRCA1 and/r BRCA2 Mutatins... 105 Research and Ptential Therapies fr Patients with Other Tumr Mutatins... 107 Therapies fr Pain and Neurpathy... 107 Therapies t Ease Depressin and Anxiety... 115 Therapies t Reduce Fatigue and Insmnia... 118 Therapies t Reduce Nausea... 122 Therapies t Increase Appetite... 124 Therapies t Increase Bne Marrw Prductin and Bld Cunts... 125 Therapies fr Cnstipatin... 128 Therapies fr Diarrhea... 129 Therapies fr Hand Ft Syndrme... 130 Therapies fr Leg r Ft Cramps... 132 Therapies fr Liver Supprt... 133 Therapies fr Muth Sres... 134 Therapies fr Ostenecrsis f the Jaw (ONJ)... 135 Therapies fr Radiated Skin... 136 Palliative Care... 137 Hspice... 138 Reference List... 139 Glssary... 140 Cnclusin... 144 Cpyright 2015 Anne Leser Updated Oct. 2017 Page 2
Dedicatin This bk is dedicated t: * My friends wh lst their lives t metastatic breast cancer, and t their lved nes and caregivers * Each persn whse life has been tuched by this disease including patients, their families, friends, & caregivers * The large grup f metastatic breast cancer patients wh have prvided helpful infrmatin that has been captured in this bk * My husband Steve, parrt Pumpkin, my friends, and my utstanding integrative health care team Abut the Authr Anne Leser is a laypersn wh has decades wrth f firsthand experience with breast cancer. She was riginally diagnsed in 1993 at age 39 with Stage II ER+/PR+ breast cancer after fur years f misdiagnsis, as the lump didn t shw up n a mammgram and r an ultrasund. She underwent chemtherapy, 5 years f Tamxifen, and 7 years f an experimental T cell vaccine which is n lnger available. Furteen years later she develped a dry chrnic cugh which three dctrs misdiagnsed as pst nasal drip r asthma. Anne cntinued t wrk as a sftware develpment prject manager fr fur years, returning hme nightly with intensifying fatigue and additinal weight lss. Thrughut the entire time, she cntinued t be checked annually by her Medical Onclgist, grateful t hear cnsistently that her Tumr Markers and ther rutine fllw up test results were cmpletely nrmal. In 2011, a few mnths after retiring, she develped harseness and visited anther specialist wh fund that ne f her vcal crds was paralyzed. A CT scan revealed the presence f multiple lung ndules, ne f which was pressing against a laryngeal nerve that in turn caused vcal crd paralysis. Further tests indicated the presence f malignant pleural and pericardial effusin, and her pathlgy reprt identified metastatic breast cancer (MBC) that was hrmne sensitive and HER2 negative. Anne s Medical Onclgist suggested that she enrll in an early Clinical Trial cnsisting f chemtherapy drugs in an unprven cmbinatin. She decided t seek a secnd pinin frm an nclgist wh prpsed that she try an Armatase Inhibitr, which was cnsistent with the hrmne receptr psitive prfile f her cancer and her pstmenpausal status. Seeking a secnd expert pinin spared her the txic side effects f chemtherapy, as well as teaching her the value ding her wn research and asking questins f her physician. Over time she als incrprated a Naturpathic Onclgist (NO) and an Acupuncturist int her health care teams. Despite being a laypersn with n medical backgrund r scientific training, Anne cntinued t cnduct research and rganize her ntes ver the curse f several years. The result is this guidebk, which has been frwarded free f charge t mre than 2,000 patients and caregivers wrldwide since its launch in 2015. Anne has als c-authred a peer-reviewed perspective article <link> regarding Atypical Patient Respnses that was published in March 2017 in Nature Partner Jurnal Breast Cancer. It is Anne s hpe that readers identify at least ne item that helps them t cpe with MBC, and that ne day a cure will be fund, rendering the need fr this bk bslete. Overview and Suggestins The purpse f this bk is t serve as a reference regarding metastatic breast cancer (MBC) and related therapies. It is nt a stry r smething that might be picked up fr entertainment purpses. Instead, it is a cmpendium f infrmatin abut MBC and related therapies that will hpefully help readers t better understand their cnditin (r that f a lved ne) alng with ptins that may be available t them. Admittedly it s US-centric because that is the cuntry in which the authr resides. Therefre, aplgies are extended t readers wh live utside the US! Varius studies are referred t thrughut the bk based upn the authr s research. Since it s nt pssible t be aware f abslutely every clinical investigatin, there may be anther study that s nt mentined which derives the ppsite result t the ne reflected herein. And there Cpyright 2015 Anne Leser Updated Oct. 2017 Page 3
may be yet anther study indicating that the results f the therapy r drug are incnclusive. S readers are strngly encuraged t d their wn research and engage their dctrs in discussins abut specific material that catches their interest. Anther imprtant pint t keep in mind is that sme supplements and therapies may interfere with cnventinal drugs r treatments. Therefre, when cnsidering new ptential therapeutic ptins, the reader shuld always cnsult with his/her dctr befre starting any new therapy r supplement. And whenever pssible, the reader is encuraged t btain a secnd (r even a third) medical pinin abut treatment, especially upn initial MBC diagnsis and when the disease prgresses (grws despite current treatment). Where pssible, hyperlinks t statistics and studies have been prvided fr ease f reference. Therefre, patients wh find smething f particular interest are encuraged t print the apprpriate sectin alng with the crrespnding hyperlink infrmatin, and discuss them with their physician. All hyperlinks are in wrking rder at the time this dcument was cmpiled, althugh it is pssible that sme may becme bslete ver time. Whenever extensive infrmatin has been prvided within a sectin, a bulleted summary is prvided at the very beginning in rder t prvide an at a glance verview f the material t fllw. The authr has deliberately mitted tw tpics: Cannabis Oil and specific Diets (such as vegan r ketgenic). The reasn fr excluding Cannabis is that there are multiple methds f preparing and ingesting it. S due t these variatins and incnsistencies - as well as legality issues - this tpic has been excluded. With respect t diet, there are nearly as many perspectives and pinins as there are MBC patients! Thse wh may be interested in diet-related infrmatin are encuraged t btain a bk by Dr. David Servain-Schreiber entitled, Anti- Cancer: A New Way f Life. Dr. David Servain-Schreiber was a physician wh lived fr nearly 20 years with a malignant brain tumr by fllwing the principles in his bk as well as cnventinal treatment. Plus it s a great read! Anther wrd abut diet: a new study frm the Mres Cancer Center at the University f Califrnia indicates that if a breast cancer patient eats at least five servings f vegetables and fruits daily and walks briskly fr 30 minutes, six days a week, her risk f death frm her disease is reduced by 50%. Althugh the study was dne n 1,490 patients with early stage breast cancer (nt MBC), it may still be ntewrthy fr advanced breast cancer patients. Frm: http://health.ucsd.edu/news/2007/pages/6-8-breastcancer-besity.aspx Althugh there are many relevant chapters in this bk, readers may find the fllwing t be f particular interest: Helpful Hints and Facts Types f Breast Cancer especially the subsectin entitled, Testing fr Hrmnal and HER2 Status Based upn yur cancer s prfile, either: Hrmne Psitive Breast Cancer, Hrmnal Therapies, and Hrmnal Therapy Resistance HER2 Psitive Breast Cancer and Related Therapies Triple Negative Breast Cancer and Related Therapies Triple Psitive Breast cancer and Related Therapies Male Breast Cancer Oligmetastasis (which refers t limited metastasis that may be highly treatable) The Micrenvirnment Persnalized Medicine Free Prfessinal Secnd Opinin MBC Cnventinal Therapies Overview Clinical Trials Overview Tumr Bipsy fr New Metastatic Sites Research and Ptentially Helpful Therapies (based upn yur cancer s prfile) Palliative Care Helpful Hints and Facts This sectin was created by a wnderful lady named Timarie f the Inspire Advanced Breast Cancer nline frum. It is reprinted belw (with sme additins) with Timarie s permissin and the authr s gratitude! 1. Always retain cpies f yur medical recrds and test results fr yur ease f reference. This includes bld tests, pathlgy reprts, clinic summaries, radilgy reprts, etc. These reprts belng t yu, and patients have learned things frm reading these reprts that their Medical Onclgists had nt mentined. Cpyright 2015 Anne Leser Updated Oct. 2017 Page 4
2. Seek a secnd r even a third - prfessinal pinin befre starting any new treatment. A secnd r third pinin can smetimes make a cnsiderable psitive difference. 3. Keep a diary f all symptms and side effects and share them with yur dctr during yu visit. If yu have a severe symptm such as difficulty breathing r swelling f the legs, g t the Emergency Rm immediately and ntify yur dctr. 4. Feel free t write dwn and bring a list f questins t discuss with yur health prvider(s) during yur visit. A knwledgeable and cnfident dctr shuld fully and clearly respnd t yur questins and cncerns. 5. When speaking with yur dctr abut yur therapy, ask him r her if there are any fds, supplements, r medicatins that yu must avid. 6. If yu will be starting chemtherapy (r are n chemtherapy and experiencing significant side effects), ask yur dctr abut the pssibility f decreasing the dsage r taking the drug less frequently. (Yu may want t review the cmpany's website where the drug sheet is listed and check fr ptential side effects and cntraindicatins). Smetimes a reduced r less frequent dsage may make a wrld f difference in cping with ptential cmfrt and pain issues. 7. If yu are in pain r any discmfrt whatsever, tell yur dctr. And if the initial prescribed pain medicatin (r ther remedy) desn t wrk, ask fr anther ptin (r a strnger dse). Cntinue this prcess until the prescribed medicatin r therapy wrks fr yu. (The sectins entitled Therapies fr Pain and Neurpathy and Palliative Care may be especially helpful fr this set f patients). 8. If yu are experiencing difficulty scheduling appintments, ask t speak t the scheduler s manager and als ntify yur physician. Generally the scheduling staff is managed separately frm the physician, s yur dctr may be unaware f hw hard a patient has t wrk t schedule an appintment at a cnvenient time. 9. Select a trusted friend r family member wh will becme yur advcate, and wh will accmpany yu t dctrs visits and treatment sessins whenever pssible. 10. There is n way t tell fr sure what treatments will wrk fr any individual persn...even thse with the exact same type f metastasis (mets) and the same hrmne receptr and HER2 status. 11. If a treatment wrks well, there is n way t predict hw lng it will cntinue t wrk. That is the reasn why patients have regular tests and fllw up visits with their Medical Onclgists. 12. There is n way t predict what side effects any individual will get with any treatment. And a lack f side effects des nt mean that the therapy is nt wrking. 13. If yur cancer has spread t ne place and then mves t yet anther part f yur bdy, it is recmmended t get the tumr(s) in the new area bipsied (if pssible) t determine whether the breast cancer in the new area has a different hrmnal and/r HER2 prfile than that in the riginal area. An example is cancer changing frm HER2- t HER2+, r frm ER-t ER+. If the prfile turns ut t be different, this can change yur recmmended treatment. 14. Bld Tumr Markers (TMs) may be an excellent indicatr f hw cancer is behaving fr sme peple and cmpletely wrthless as an indicatr fr thers. And in sme instances, TMs may start ff being accurate and then stp being accurate. 15. Patients may be candidates fr hrmnal therapy irrespective f their hrmne receptivity status, prvided that their cancer is in the bnes, sft tissue (muscle, fat r nerves), r internal rgans and is nt causing symptms. This is because smetimes the metastasis is indeed hrmne receptr psitive and the test results are incrrect, and als due t the fact that breast cancer can be hetergeneus (fr example, sme cells may be hrmne receptr negative and thers may be hrmne receptr psitive). (Mre abut this is in the sectin entitled, Types f Breast Cancer. ) 16. Hrmnal therapy fr hrmne psitive patients is nt a less aggressive r a weaker treatment than chemtherapy ( chem ). Althugh hrmnal therapy ften has fewer and mre tlerable side effects than chem, it can be as - r even mre - effective in certain patients. Fr patients whse cancer is ER and/r PR psitive (r have an unknwn hrmnal status) and wh are nt experiencing acute symptms, hrmnal therapy is usually a gd first chice. Unfrtunately nt all hrmne psitive patients may respnd t anti-hrmne treatments. Cpyright 2015 Anne Leser Updated Oct. 2017 Page 5
17. Sme patients whse breast cancer is cnsidered Hrmne Receptr (HR) negative and/r HER2 negative may have been misclassified based upn their test results. Additinal infrmatin abut this is prvided in sectin entitled Types f Breast Cancer under Testing fr Hrmnal and HER2 Status. 18. Patients whse Tumr Markers and/r scans shw prgressin may want t ask their dctr abut delaying a treatment change until a subsequent test a mnth r tw thereafter cnfirms the cntinuance f prgressin. The pssibility f deferring a change in treatment shuld nly be cnsidered if 1) the prgressin is nt life-threatening, 2) it is nt causing symptms r cmplicatins, r 3) it is nt cnsidered by the dctr t be significant enugh t warrant immediate change. One patient taking Ibrance and Fasldex nted that her cancer remained stable fr 5 cycles (abut 4 mnths), at which pint her CT results shwed prgressin in the liver. Her nclgist felt that the treatment shuld be changed, but due t an unfreseen delay, her treatment was nt altered. Tw mnths thereafter, a fllw up CT shwed stable disease, s she has remained n this treatment fr 11 cycles (abut 11 mnths) thus far and her tests cntinue t shw stable disease. 19. Nt just wmen get breast cancer; men can get it as well, althugh it is rarer (nly abut 1% f all patients are male) 20. Mst MBC patients start with metastasis ( mets) in their bnes as ppsed t their lungs, liver, brain r elsewhere. 21. Because it desn t shw up as a slid tumr and lks mre like a spider web, Lbular metastatic breast cancer may difficult t diagnse and track. It als has a tendency t metastasize (spread) t the abdminal area, s patients with lbular breast cancer shuld be especially practive in reprting pain r abdminal swelling t their dctr. 22. Patients abut t g n the chem drugs Xelda r 5-FU shuld first speak with their dctr abut getting tested fr specific mutatins in the DPD (dihydrpyrimidine dehydrgenase) gene that culd cause severely txic r ptentially life-threatening reactins t these drugs. Apprximately 3% t 8% f the ppulatin has sme degree f DPD deficiency that can put them at risk if they take these drugs. 23. Since chemtherapy and varius targeted therapies such as Herceptin (Trastuzumab) can ptentially cause damage t the heart, liver, lungs, and/r kidneys, patients shuld ensure that their dctr is fully aware f any existing issues regarding these areas, and that they will be carefully mnitred while taking these drugs. 24. Peple receiving shts f any kind (including but nt limited t Fasldex r Xgeva) shuld request that the vaccine be warmed first and then injected slwly. This will help t minimize pain immediately fllwing the injectin and in the days thereafter. 25. Patients receiving sterids as part f their treatment, such as chemtherapy r radiatin therapy, are mre susceptible t getting cataracts. Therefre, patients n these regimens shuld be especially diligent abut reprting cular changes and getting rutine eye exams. 26. Fr patients wh are diagnsed with metastatic breast cancer withut previusly having early stage breast cancer, recent research indicates that surgery t remve the primary tumr may extend survival. Frm: http://www.eurekalert.rg/pub_releases/2016-06/ups-itc060116.php 27. In additin t ER, PR and HER2 therapies, Andrgen Receptr (AR) therapies may be prmising, and clinical trials are underway t test the efficacy f AR-targeting drugs. Research indicates that 88% f estrgen-psitive breast cancers, 50% f HER2+ breast cancers, and 25% f triple-negative breast cancers (TNBC) are Andrgen-Receptr psitive, making Andrgen Receptrs a pssible target fr many breast cancers. Mre infrmatin abut AR therapies can be fund in the sectin entitled Research and Ptentially Helpful Therapies. 28. Similar t ptentially targeting Andrgen Receptrs, FGFR1 and/r 11q amplificatins have been fund in all subtypes f MBC, making them targets fr emerging therapies. Research has fund that 23% f estrgen-psitive breast cancers, 27% f HER2+ breast cancers, and 7% f triple-negative breast cancers (TNBC) test psitive fr these factrs. Mre infrmatin abut ptential therapies fr these targets can be fund in the sectin entitled Research and Ptentially Helpful Therapies. 29. If yu are interested in a Clinical Trial, yu may want t call 1.800.4.CANCER (1.800.422.6237). A knwledgeable representative will cnduct a free custmized search fr yu based upn yur cancer s prfile (i.e. ER, PR and HER2 status) as well as yur particular interests such as immuntherapy, chemtherapy, hrmnal therapy, targeted therapy, etc. 30. Please d nt pay much attentin t statistics! Nne f us has an expiratin date, and many peple with MBC will live fr many years...far lnger than statistics might lead ne t believe. Hw lng yu live seems t be mstly dependent n hw well yur cancer Cpyright 2015 Anne Leser Updated Oct. 2017 Page 6
respnds t varius treatments, and sme peple als believe that lifestyle may play a helpful rle in survival. Many MBC patients wh were given nly mnths t live are still alive years later. Types f Breast Cancer and Related Tests If breast cancer is suspected, a bipsy (remval f tissue) will be dne t check t determine what, if any, type f breast cancer is present. Patients wh are already aware f the type f breast cancer they have - such as Invasive Ductal Carcinma - may prefer t skip a few pages t read abut TESTS FOR HORMONAL STATUS. Patients wh may nt knw what type f breast cancer they have are encuraged t review the fllwing sectin and ask their dctr which type f breast cancer they were diagnsed with. This is imprtant because sme types f breast cancer, such as Invasive Lbular Carcinma, tend t metastasize t parts f the bdy that ther types f breast cancers generally avid. Therefre, patients with this frm f breast cancer need t be especially vigilant in identifying and reprting related symptms t their dctr. TYPES OF BREAST CANCER On a very general level, nce breast cancer is fund, it is categrized as either Nn-Invasive r Invasive: Nn-Invasive Breast Cancer (als knwn as Carcinma In Situ) is when cancer is fund inside the milk ducts r lbules, but it appears nt t have spread t nearby tissue r beynd. This may als be referred t as pre-invasive breast carcinma. In situ breast cancer can subsequently develp int invasive breast cancer. On ccasin, peple diagnsed with in situ breast cancer have subsequently been fund t have breast cancer elsewhere in the bdy. There are Tw Cmmn Types f Nn-Invasive Breast Cancer (Carcinma In Situ): Ductal Carcinma in Situ Lbular Carcinma in Situ Ductal Carcinma In Situ (DCIS) is the mst cmmn type f nn-invasive breast cancer. Ductal means that the cancer starts inside the milk ducts, and in situ means that the abnrmal grwth remains inside milk duct and appears nt t have spread t surrunding tissues. Having DCIS can increase the risk f develping an invasive breast cancer later n. Mst recurrences happen within the 5 t 10 years after initial diagnsis, and the chance f a recurrence is under 30%. Lbular Carcinma in Situ (LCIS) is an area(s) f abnrmal cell grwth that increases a persn s risk f subsequently develping invasive breast cancer. Lbular means that the abnrmal cells start grwing in the lbules, which are the milkprducing glands at the end f breast ducts. In situ means that the abnrmal grwth remains inside the lbule and appears nt t have spread t surrunding tissues. Peple diagnsed with LCIS may tend t have mre than ne lbule affected. LCIS des nt cause symptms and usually des nt shw up n a mammgram, s it tends t be diagnsed as a result f a bipsy perfrmed fr sme ther reasn. Invasive Breast Cancer refers t when abnrmal cells break ut f the lbules r milk ducts and mve int nearby breast tissue and/r lymph ndes. Cancer cells can travel frm the breast t ther parts r rgans f the bdy ( metastasize ) thrugh the bld stream r the lymphatic system. Cancer cells may travel early when the tumr is small, r later when the tumr is large. There are many types f Invasive Breast Cancer as described belw. Invasive Ductal Carcinma: Abut 70% t 80% f all breast cancers are Invasive (r Infiltrative) Ductal Carcinma (IDC), where the abnrmal cancer cells that began in the milk ducts have spread int ther parts f the breast tissue and pssibly beynd. Frm: http://www.natinalbreastcancer.rg/invasive-ductal-carcinma Specific sub-types f Invasive Ductal Carcinma (IDC) include: Invasive Carcinma f N Special Type (NST) r Nt Otherwise Specified (NOS) Invasive Cribrifrm Carcinma Invasive Papillary Carcinmas f the Breast Medullary Carcinma f the Breast Mucinus Carcinma f the Breast Tubular Carcinma f the Breast Cpyright 2015 Anne Leser Updated Oct. 2017 Page 7
Invasive Carcinma f N Special Type (NST) r Nt Otherwise Specified (NOS), which is the mst cmmn frm f invasive breast cancer. It accunts fr 55% f breast cancer incidence upn diagnsis. Smetimes this type f cancer is simply referred t as Infiltrating Ductal Carcinma. Invasive Cribrifrm Carcinma is a type f breast cancer in which the cancer cells invade the strma (cnnective tissues f the breast) in nest-like frmatins between the ducts and lbules. Within the tumr, there are distinctive hles in between the cancer cells, making the tumr resemble swiss cheese. Invasive cribrifrm carcinma is usually lw grade. In abut 5%-6% f invasive breast cancers, sme prtin f the tumr can be cnsidered cribrifrm. Usually, sme DCIS f the cribrifrm type is als present. Invasive Papillary Carcinmas f the Breast accunts fr less than 1-2% f invasive breast cancers. Invasive papillary carcinma usually has a well-defined brder and is made up f small, finger-like prjectins. In mst cases f invasive papillary carcinma, ductal carcinma in situ (DCIS) is als present. Medullary Carcinma f the Breast represents abut 3-5% f all breast cancers. It is called medullary because the tumr is a sft, fleshy mass that resembles a part f the brain called the medulla. It s mre cmmn in wmen wh have a BRCA1 mutatin. The cells are usually high-grade in their appearance and lw-grade in their behavir. S whereas they lk like aggressive abnrmal cancer cells, they dn t usually act like them. Medullary carcinma may typically be easier t treat than ther types f breast cancer. Mucinus Carcinma f the Breast smetimes called cllid carcinma is a rare frm f invasive ductal carcinma. In this cancer, the tumr is made up f abnrmal cells that flat in pls f mucin, a key ingredient in the slippery substance knwn as mucus. In mucinus carcinma, the mucin becmes part f the tumr and surrunds the breast cancer cells. Under a micrscpe, it lks like the cancer cells are scattered thrughut pls f mucus. Only abut 2-3% f invasive breast cancers are pure mucinus carcinmas; abut 5% f invasive breast cancers appear t have a mucinus cmpnent within them, alng with ther types f cancer cells present. Overall, it is a less aggressive type that respnds well t treatment. Tubular Carcinma f the Breast is usually small and made up f tube-shaped structures called "tubules." These tumrs tend t be lw-grade and slw-grwing. Studies suggest that tubular carcinmas may accunt fr anywhere frm just under 8% t 27% f breast cancers. It tends t be less aggressive and respnds well t treatment. In additin t the types f Invasive Ductal Carcinma described abve, additinal categries f Invasive Breast Cancers include: Inflammatry Breast Cancer (IBC) Invasive Lbular Carcinma (ILC) Paget s Disease f the Nipple Phylldes Tumrs f the Breast Inflammatry Breast Cancer (IBC) is a rare and aggressive frm f breast cancer. Only abut 1% t 5% f all breast cancer cases in the US are inflammatry breast cancers. IBC usually starts with the reddening and swelling f the breast instead f a lump. It tends t grw and spread quickly, with symptms wrsening within days r even hurs. It is imprtant t recgnize these symptms and seek prmpt medical treatment. Invasive Lbular Carcinma (ILC) starts in the breast lbules (the areas f the breast that prduce milk). ILC is the secnd mst cmmn type f breast cancer, ccurring in 10% f all breast cancer cases. It is usually estrgen and prgesterne psitive and HER2 receptr negative (althugh it may harbr a HER2 and/r HER3 mutatin), and appears t derive particular benefit frm treatment with armatase inhibitrs cmpared with tamxifen. Frm: http://jc.ascpubs.rg/cntent/early/2016/03/23/jco.2015.66.3872 ILC may appear mre like a spider web r filmy sheets than a slid tumr, and therefre it is frequently difficult t diagnse and track because it des nt always appear n scans. This type f cancer may ften spread t the vary, abdmen/stmach, peritneum (the tissue that lines the abdminal wall and cvers rgans in the abdmen), and mentum (a membranus duble layer f fatty tissue that cvers the intestines and rgans in the lwer abdmen). Smetimes the functin f the ureters and bile ducts can als be impacted. On ccasin, excess fluid called ascites may build up in the abdminal area. Because ILC des nt lk like a slid tumr, ne cannt cmpletely rule it ut - even despite negative scans and test results - especially when Tumr Markers (TMs) are unreliable and the patient is experiencing symptms. Sme peple with ILC experience significant issues such as fatigue, weight lss, nausea, abdminal pain r extensin ( lking pregnant ), diarrhea, lss f appetite, and /r a feeling f premature fullness while eating. One wman with lbular metastatic cancer and ascites wrte, Only when I had a Cpyright 2015 Anne Leser Updated Oct. 2017 Page 8
Clnscpy and EsphaGgastrDudenscpy (EGD) with a bipsy did the bipsies reveal the cancer. S if ILC is suspected, an EGD, clnscpy, and ther tests may be helpful in diagnsing and tracking it. An uncmmn subtype f ILC is called Plemrphic Lbular Carcinma. The term Plemrphic refers t a wide variability in the size, shape and staining f cells and/r their nuclei. Plemrphic ILC accunts fr abut 1% f all Invasive Lbular Carcinmas, predminantly affects pstmenpausal wmen between the ages f 60 t 80, and tends t be mre aggressive. Plemrphic lbular carcinma can exhibit mlecular aberratins assciated with classical lbular carcinma and even IDC, such as p53 psitivity, verexpressin f HER2/neu, changes in E-cadherin prtein functin, and c-myc (which is a grwth regulating gene). The aggressive bilgy f plemrphic lbular carcinma relates t the acquisitin f these genetic alteratins. Frm: http://www.archivesfpathlgy.rg/di/pdf/10.5858/arpa.2012-0603-rs?cde=cap-site In general, ILC breast cancers are hrmne receptr psitive, HER2 negative, and are characterized by a lss f E-cadherin (Epithelial cadherin). E-cadherin is an imprtant determinant f tumr prgressin, serving as a suppressr f invasin and metastasis in many cntexts. Because ILC mre clsely resembles a filmy sheet rather than a slid tumr, it is mre difficult t diagnse and track than IDC. ILC exhibits a prpensity t gravitate t less cmmn areas, such as the GI tract. Interestingly, as per the BIG1-98 study, patient with ILC appear t respnd better t armatase inhibitrs than t Tamxifen, and it has been stated that ILC tends nt t respnd favrably t chemtherapy. A ntable subset f ILC cancers cntain a FGFR mutatin fr which targeted drugs are being tested in the clinical trial setting as f Octber 2017. Frm: https://jeccr.bimedcentral.cm/articles/10.1186/1756-9966-31-103 Patients with ILC may be interested in visiting the newly-frmed Lbular Breast Cancer Alliance at https://lbularbreastcancer.rg/ Paget's Disease f the Nipple is a rare frm f breast cancer in which cancer cells cllect in r arund the nipple. The cancer usually affects the ducts f the nipple first and then spreads t the nipple surface and the arela (the dark circle f skin arund the nipple). The nipple and arela ften becme scaly, red, itchy, and irritated. Paget's disease f the nipple accunts fr less than 5% f breast cancer. Being aware symptms is imprtant, given that mre than 97% f peple with Paget's disease als have cancer, either DCIS r invasive, smewhere else in the breast. Phylldes Tumrs f the Breast are rare, accunting fr less than 1% f all breast tumrs. The name "phylldes" means "leaf like," and refers t that fact that the tumr cells grw in a leaf like pattern. Phylldes tumrs tend t grw quickly, but they rarely spread utside the breast. Althugh mst phylldes tumrs are benign, sme are malignant and thers are cnsidered brderline. Phylldes tumrs tend t grw quickly, and they require surgery t reduce the risk f a phylldes tumr cming back in the breast (lcal recurrence). Mst infrmatin abve is Frm: http://www.breastcancer.rg/symptms/types/idc/tests/diagnsing TESTS FOR HORMONAL STATUS When breast cancer cells are fund and categrized as described abve, the additinal tests listed belw will be undertaken in rder t determine hrmnal receptivity (specifically, Estrgen Receptivity [ER] and Prgesterne Receptivity [PR]), alng with HER2neu receptivity. The utcme will help t determine the type f treatment(s) the patient will receive: Hrmne Receptivity (HR) Tests: A hrmne receptr is a specialized prtein lcated n the surface f r within a cell. The hrmne receptr binds t the female hrmnes Estrgen (ER) and/r Prgesterne (PR), which flw thrugh the bld. Once bund, the hrmne signals the cell t start grwing and multiplying. Mst testing labs use a special staining prcess that makes the hrmne receptrs shw up in a sample f breast cancer tissue. The test is called an ImmunHistChemical (IHC) staining assay. When hrmne receptrs are present, estrgen and/r prgesterne can fuel the grwth f breast cancer. If either r bth the ER and/r PR receptr is fund t be psitive, the breast cancer is classified as hrmne receptr psitive. (In the rare instances hrmnal test results are incnclusive, the patient shuld nevertheless be initially treated with hrmnal therapy). Hrmne receptrs are present in the majrity f bth early- and late-stage breast cancers, with expressin fund in apprximately 65% t 70% f metastatic tumrs. Hw the hrmne receptivity test results appear in a patient s pathlgy reprt may vary. Nt all labs use the same methd fr analyzing the results f the test, nr d they have t reprt the results in exactly the same way. Generally, hrmnal testing results are prvided in ne f the fur ways listed belw: Cpyright 2015 Anne Leser Updated Oct. 2017 Page 9
Allred Scre Between 0 and 8: The lab may use an Allred scre between 0 and 8. This technique lks at the percentage f cells that test psitive fr hrmne receptrs, as well as hw well the receptrs shw up after staining (this is called intensity ). The percentage and intensity factrs are cmbined t give a scre between 0 and 8. The higher the scre, the mre receptrs were fund and the easier they were t see in the sample. Number Between 0 and 3: 0 means that n ER and r PR receptrs are present. 1 indicates that a small number are present. 2 means that a mderate number are present, and 3 represents a large number are present. Percentage: The results may appear as a percentage that indicates hw many cells ut f 100 stain psitive fr hrmne receptrs. The lab will prvide a number between 0% (n cells have receptrs) and 100% (all cells have receptrs). Psitive r Negative: The lab may simply state the hrmne receptr status is Psitive r Negative. If the lab result is reprted as just the wrd psitive r negative, patients shuld ask their dctr fr a mre definite percentage. Different labs have different cutff pints fr calling the cancer either hrmne-receptr-psitive r hrmne-receptr-negative. Fr example, if between 1% and 9% f the cells stain psitive (a categry called brderline int which 6% f all breast cancers fall), ne lab might call this a psitive result whereas anther lab may declare it a negative result. That said, verall, the mst cmprehensive breast cancer studies have cnsistently shwn that levels as lw as 1% psitive-staining carcinma cells are assciated with significant clinical respnse. Frm: http://www.archivesfpathlgy.rg/di/pdf/10.1043/1543-2165-134.6.907 Sme research studies (such as the ne immediately belw) have shwn that ANY psitive results, n matter hw lw (even in the brderline 1% t 9% psitive categry), mean that the patient might be a candidate fr hrmnal therapy. A scre f 0% wuld be needed t cmpletely rule ut hrmnal therapy as a ptential treatment (and even then, there may be exceptins as per the third bullet). Frm: http://www.breastcancer.rg/symptms/testing/types/ihc and pages 911 and 913 f http://www.archivesfpathlgy.rg/di/pdf/10.1043/1543-2165-134.6.907 In a study f 465peple with MBC, 6 (r 24%) f the 25 patients wh were placed in the in the 1% t 9% ( brderline ) Estrgen Receptr (ER) psitive categry based upn their IHC test, ended up being classified as ER psitive when tested by ESR1 mrna expressin (which is cnsistent with ER psitive status). In the same study, 4 (r 67%) f the 6 patients in exactly the 10% ER psitive categry had ER-assciated gene signature scres that were cnsistent with ER-psitive status. Finally, in 16 (r 9%) f the 183 patients whse tumrs had tested at abslute 0% fr ER receptivity, the study fund a gene signature that was cnsistent with ER psitive status. Frm: http://jc.ascpubs.rg/cntent/30/7/729.lng Accrding t the latest (2014) Natinal Cmprehensive Cancer Netwrk (NCCN) Guidelines, Patients may be candidates fr hrmnal therapy irrespective f their hrmne receptivity status, prvided that their cancer is in the bnes, sft tissue (muscle, fat r nerves), r internal rgans and is nt causing symptms. The reasn fr suggesting hrmnal therapy is because smetimes the metastasis is indeed hrmne receptr psitive and the actual test results are incrrect. Therefre, hrmne receptr negative patients and their dctrs shuld cnsider hrmnal therapy especially if the patient had a lng disease free perid after initial treatment, if their cancer is cnfined t ne r few sites, and their cancer is nt causing symptms. (This represents a majr shift in thinking regarding ptential therapies fr TNBC and hrmne receptr negative patients). Frm: http://www.nccn.rg/patients/guidelines/stage_iv_breast/index.html#33/z TESTS FOR HER2 STATUS Testing fr Whether Breast Cancer is HER2 Psitive r Negative: Similar t the hrmne receptr test described abve, the HER2 neu test lks fr a specific kind f prtein that is fund with certain types f cancer cells, alng with the gene that prduces that prtein. The frmal name f that gene is the human epidermal grwth factr receptr 2, which makes HER2 prteins that are receptrs n breast cells. Healthy HER2 receptrs are the prteins that help manage hw a breast cell grws, divides, and repairs itself. But in abut 25% f all breast cancer patients, the HER2 gene isn t functining prperly. Instead, it makes t many cpies f itself in a prcess knwn as HER2 gene amplificatin, which results in t many HER2 receptrs. (This is smetimes referred t as HER2 prtein verexpressin). The result is that these breast cells grw and divide in an uncntrlled fashin, and the patient s cancer is cnsidered HER2+ (psitive). Hw the HER2 test results appear in a patient s pathlgy reprt will depend n what specific HER2 test is dne. There are fur pssible tests fr HER2: Cpyright 2015 Anne Leser Updated Oct. 2017 Page 10
FISH Test IHC Test Infrm HER2 Dual ISH Test SPT-Light HER2 CISH Test FISH (Flurescence In Situ Hybridizatin) Test: The Flurescence In Situ Hybridizatin test finds ut if there are t many cpies f the HER2 gene in the cancer cells. The results f the FISH test can be psitive (HER2 gene amplificatin) r negative (n HER2 gene amplificatin). IHC test (ImmunHistChemistry): The ImmunHistChemistry test finds ut if there is t much HER2 prtein in the cancer cells. The results f the IHC test can be: 0 (negative), 1+ (als negative), 2+ (brderline), r 3+ (psitive HER2 prtein verexpressin). Infrm HER2 Dual ISH Test (Infrm Dual In Situ Hybridizatin): The Infrm HER2 Dual ISH test finds ut if there are t many cpies f the HER2 gene in the cancer cells. The results f the Infrm HER2 Dual ISH test can be psitive (HER2 gene amplificatin) r negative (n HER2 gene amplificatin). SPT-Light HER2 CISH Test (Subtractin Prbe Technlgy Chrmgenic In Situ Hybridizatin): The SPT-Light test finds ut if there are t many cpies f the HER2 gene in the cancer cells. The results f the SPT-Light test can be psitive (HER2 gene amplificatin) r negative (n HER2 gene amplificatin). The latest (2013) ASCO HER2 Testing Guidelines advise clinicians t use a bright-field ISH (the latter tw test types). This technique als evaluates fr amplificatin f the HER2 gene, and uses a regular light micrscpe rather than a flurescent micrscpe. Frm: http://www.asc.rg/press-center/asc-and-cap-release-updated-guideline-her2-testing-breast-cancer ASCO 2013 guidelines specifically define HER2-psitive status as ccurring when (n bserving within an area f tumr that amunts t > 10% f cntiguus and hmgeneus tumr cells) there is evidence f prtein verexpressin (IHC) r gene amplificatin (HER2 cpy number r HER2/CEP17 rati by ISH based n cunting at least 20 cells within the area). If results are equivcal (uncertain), reflex testing shuld be perfrmed using an alternative assay (IHC r ISH). Repeat testing shuld be cnsidered if results seem discrdant with ther histpathlgic findings. Frm: http://jc.ascpubs.rg/cntent/31/31/3997.abstract?ijkey=69fc153977e84d4b3e0333953a9d7fa0a62d119f&keytype2=tf_ipsec sha It is imprtant fr patients t knw which HER2 status test is dne. Generally, nly cancers that test IHC 3+, FISH psitive, SPT-Light HER2 CISH psitive, r Infrm HER2 Dual ISH psitive respnd t the medicines that target HER2-psitive breast cancers. An IHC 2+ test result is called brderline. If a patient has an IHC 2+ result, s/he may be wise t have the tissue retested with a mre precise HER2 test such as the FISH test, SPT-Light HER2 CISH test, r the Infrm HER2 Dual ISH test. Frm: http://www.breastcancer.rg/symptms/diagnsis/her2 IMPORTANT NOTE! Accrding t the Cllege f American Pathlgy (CAP), Labratry assays fr HER2, Estrgen Receptr and Prgesterne Receptr are essential in selecting patients fr anti-her2 and hrmnal therapy, yet inaccuracies in testing pse a significant prblem in ensuring that patients are treated apprpriately. Frm: http://www.cap.rg/apps/dcs/cmmittees/immunhistchemistry/her2_faqs.pdf Therefre, befre having surgery t btain a bipsy, patients bth in the US and internatinally - shuld wrk with their dctrs t send the tumr sample t a labratry that is Cllege f American Pathlgy (CAP) Certified if at all pssible, since CAP is the gld standard fr labratry accreditatin. Patients and their dctrs may search fr a list f CAP-Certified Labratries at: http://www.cap.rg/apps//cap.prtal?_nfpb=true&_pagelabel=accrlabsearch_page And whenever pssible, patients shuld schedule their bipsy n a mrning early in the week t minimize the ptential fr specimen mishandling. (Additinal details abut the pitfalls besetting tumr testing are prvided in the sectin entitled, Tumr Bipsy fr New Metastatic Sites ). TNBC: Patients whse breast cancer cells have neither hrmne receptrs nr HER2 prtein amplificatin, have what is called Triple Negative Breast Cancer (TNBC) r Basal Like breast cancer. TNBC accunts fr abut 10% t 20% f all breast cancer, and usually the Cpyright 2015 Anne Leser Updated Oct. 2017 Page 11
mst challenging t treat. That said, patients initially classified as TNBC are encuraged t duble-check their Hrmne Receptr and HER2 pathlgy tests t determine whether these tests need t be re-taken in rder t btain mre specificity. Fr example, it is pssible that sme patients initially classified as hrmne receptr negative may fall int the brderline hrmne receptive psitive grup and therefre be ptential candidates fr hrmnal therapy. THE 4 CATEGORIES OF BREAST CANCER Once a patient s breast cancer has been tested fr hrmne and HER2 receptrs, it is categrized int ne f the fllwing fur grups: Luminal A: This grup includes tumrs that are bth ER and PR psitive, but negative fr HER2. Luminal A breast cancers are likely t benefit frm hrmne therapy and they may als benefit frm chemtherapy and sme targeted therapy. Detailed infrmatin fr Luminal A breast cancer patients is prvided in the sectin entitled, Hrmne Psitive Breast Cancer, Hrmnal Therapies, and Hrmnal Therapy Resistance. Luminal B: This type includes tumrs that are ER psitive and/r PR psitive, and either HER2 psitive r HER2 negative with a high Ki67 scre (Ki67 is an antigen [r prtein] that sits n the surface f a cell and stimulates the prductin f an antibdy. The best Ki67 index cut pint t distinguish luminal B frm luminal A tumrs was 13.25%. Frm: http://jnci.xfrdjurnals.rg/cntent/101/10/736.full ). Luminal B breast cancers may benefit frm hrmne therapy, chemtherapy and /r targeted therapy. Detailed infrmatin fr Luminal B breast cancer patients wh are ER and/r PR psitive and HER2 negative is prvided in the sectin entitled, Hrmne Psitive Breast Cancer, Hrmnal Therapies, and Hrmnal Therapy Resistance. Infrmatin fr Luminal B breast cancer patients wh are ER and/r PR psitive and HER2 psitive (Triple Psitive) is prvided in the sectin entitled, Triple Psitive Breast Cancer and Related Therapies. HER2 + This type f breast cancer includes tumrs that are ER negative and PR negative, and HER2 psitive. HER2 + breast cancers are likely t benefit frm treatment that is specifically targeted t HER2, alng with chemtherapy. Detailed infrmatin fr patients with this type is f breast cancer is prvided in the sectin entitled, HER2 Psitive Breast Cancer and Related Therapies. Basal Like (Triple Negative Breast Cancer, r TNBC ): This type f breast cancer includes tumrs that are ER negative, PR negative and HER2 negative. Basal-like breast cancers are likely t benefit frm chemtherapy and ptentially sme targeted therapy. Additinal infrmatin fr patients with this type f breast cancer is prvided in the sectin entitled, Triple Negative Breast Cancer and Related Therapies. Frm: http://www.mayclinic.rg/diseases-cnditins/breast-cancer/in-depth/breast-cancer/art-20045654?pg=2 and http://www.dslrf.rg/breastcancer/cntent.asp?catid=18&l2=3&l3=7&l4=0&pid=&sid=132&cid=577 Sme researchers are cntinuing t identify additinal sub-categries f breast cancer. A recent study called METABRIC cnducted an extensive assessment f breast cancer tumrs, and re-classified them int 10 distinct sub-types as ppsed t the fur categries mentined abve. Detailed infrmatin abut this study is prvided in the sectin entitled, Research and Ptential Therapies fr All Categries f Breast Cancer. Hrmne Psitive Breast Cancer, Hrmnal Therapies, and Hrmnal Therapy Resistance Hrmne receptrs are present in the majrity late-stage breast cancers, with expressin fund in apprximately 65% t 70% f metastatic tumrs. Breast cancers that are Estrgen Receptr (ER) psitive and/r Prgesterne Receptr (PR) psitive are cnsidered Hrmne Receptr (HR) psitive (unless their cancer is als HER2 psitive [ Triple Psitive ] and fr which distinct treatment guidelines exist as described in the sectin entitled, Triple Psitive Breast Cancer and Related Therapies ). In the rare instances when the hrmne receptr status f a patient is unknwn because the tumr may nt be bipsy-able, r repeated test results are incnclusive, hrmnal therapy is usually recmmended as first line therapy. Frm: http://www.dslrf.rg/breastcancer/cntent.asp?catid=18&l2=3&l3=7&l4=0&pid=&sid=132&cid=577 and http://www.cancer.gv/cancertpics/pdq/treatment/breast/healthprfessinal/page6#_211_tc Patients with the type f breast cancer described in this chapter usually are classified as having Luminal A MBC, althugh sme Luminal B patients may fit this prfile. These Luminal B patients are ER psitive and/r PR psitive, and HER2 negative (but with a high Ki67 scre, unlike Luminal A breast cancer). In many cases, patients with hrmne receptr psitive breast cancer respnd well t hrmnal therapies. The cncept behind hrmnal ( endcrine ) therapy is t starve the cancer cells f the estrgen hrmne they need in rder t thrive. Except fr the caveats belw, Cpyright 2015 Anne Leser Updated Oct. 2017 Page 12
hrmnal therapies are nrmally the first-line therapy fr bth premenpausal and pstmenpausal patients, even when there is visceral disease (i.e. disease in the sft internal rgans such as the lung r liver). Althugh hrmnal therapy may generally take a little lnger t wrk than chemtherapy, it can be as r mre effective in sme ppulatins. Mst hrmnal therapies are given in pill frm, althugh Fasldex is administered as an injectin. Caveats: Patients experiencing cnsiderable symptms r life-threatening disease, wh have majr liver invlvement, Central Nervus System (CNS) invlvement, multiple tumrs in the lung s lymphatic system, wh have had early failure n hrmne therapy (less than 6 mnths) r have been ff adjuvant hrmnal therapy fr less than a year shuld cnsider chemtherapy and/r ther therapies (pssibly with hrmnal therapy) instead f hrmnal therapy alne. When determining a patient s therapy, dctrs als need t take int accunt where the patient s cancer has spread because there are ften additinal therapies that may be warranted (fr example, patients with bne metastases shuld als be given a bne-directed therapy such as Xgeva [Densumab] r Zmeta [Zledrnic Acid]). Frm: http://www.ascpst.cm/issues/ctber-15,-2014/asc-clinical-practice-guideline-chemtherapy-and-targeted-therapyin-advanced-her2-negative-r-her2-status%e2%80%93unknwn-breast-cancer.aspx and http://www.cancer.gv/cancertpics/pdq/treatment/breast/healthprfessinal/page6#_211_tc Accrding t ASCO 2016 guidelines, genmic r expressin prfiling shuld nt be used t select initial treatments fr metastatic hrmne psitive breast cancer. Frm: http://www.medscape.cm/viewarticle/864032?src=wnl_edit_tpal&uac=68373mk Hrmnal therapy fr premenpausal wmen and pstmenpausal patients differs smewhat as described belw, and the use f a specific agent can be repeated if recurrence happens mre than 12 mnths after the last treatment. Frm: http://www.medscape.cm/viewarticle/864032?src=wnl_edit_tpal&uac=68373mk Readers are highly encuraged t review the sectins n Hrmnal Therapy and Targeted Therapy fr detailed and imprtant infrmatin. HORMONAL THERAPIES FOR PREMENOPAUSAL PATIENTS Hrmnal Therapy Drugs fr Premenpausal Patients A list f hrmnal therapy drugs fr premenpausal patients appears belw, and additinal detail is lcated in the sectin entitled Hrmnal Therapy. Zladex (Gserelin), Luprn (Leuprlide), r Trelstar (Triptrelin) fr varian suppressin Tamxifen (Nlvadex) and Tremifene (Farestn), which are Selective Estrgen Receptr Mdulatrs, r SERMs. SERMs wrk by sitting in the estrgen receptrs in breast cells. If a SERM is sitting in the estrgen receptr, there is n rm fr estrgen and it can't attach t the cell. If estrgen isn't attached t a breast cell, the cell desn't receive estrgen's signals t grw and multiply. Tamxifen is mre widely used than Farestn in the US, althugh fr premenpausal patients with flaws in their CYP2D6 genetic pathway, Farestn is a better chice than Tamxifen because it des nt rely n this pathway t be effective (mre abut Tamxifen and CYP2D6 under Pssible Causes fr Hrmnal Therapy Resistance in this chapter). A subset f individuals with metastatic breast cancer may experience a "flare" f their breast cancer within tw days t three weeks after starting tamxifen. This may cause an increase in bne pain, a high bld calcium level, and in individuals with breast cancer invlving the skin, an increase in the size and/r number f these skin ndules, r skin redness. These flares usually subside within fur t six weeks. In the meantime, the symptms can be treated with measures that reduce pain and lwer bld levels f calcium. Frm: http://www.uptdate.cm/cntents/treatment-f-metastatic-breast-cancerbeynd-the-basics Hrmnal Therapy Sequence fr Premenpausal Patients In general, the sequence f prviding hrmnal therapy fr premenpausal wmen is as fllws: Upn diagnsis, a Luteinizing Hrmne-Releasing Hrmne (LHRH) agnist such as Zladex, Luprn r Trelstar is recmmended alng with a hrmnal therapy fr pstmenpausal patients. (LHRH agnists wrk by telling the pituitary gland lcated in the brain t stp prducing luteinizing hrmne, which in wmen stimulates the varies t release estrgen. The drug des nt have a direct effect n breast cancer, nly n the varies. The resulting lack f estrgen interferes with stimulating cell grwth in estrgen-dependent cancer cells. Fr female mbc patients, varian ablatin (remval f the varies, called Cpyright 2015 Anne Leser Updated Oct. 2017 Page 13
pherectmy ) may be substituted fr an LHRH agnist, in which case the patient becmes fully pstmenpausal and shuld fllw the hrmnal therapy guidelines fr pstmenpausal patients. Tamxifen (r Farestn) may be given alne as a first line therapy fr premenpausal patients, althugh it is mre cmmn fr it t be paired alng with an LHRH agnist. After prgressin (when the cancer has begun t grw again despite treatment), if a female mbc patient still has her varies, varian ablatin (remval f the varies, called pherectmy ) may apprpriate as secnd-line therapy because it remves a substantial surce f estrgen frm being prduced by the bdy. At that pint, the wman is cnsidered pstmenpausal and shuld fllw the hrmnal therapy guidelines fr pstmenpausal patients. HORMONAL THERAPIES FOR POSTMENOPAUSAL PATIENTS Hrmnal Therapy Drugs fr Pstmenpausal Patients: A list f hrmnal therapy drugs fr pstmenpausal wmen is as fllws (additinal detail is lcated in the sectin entitled Hrmnal Therapy. Armatase Inhibitrs (AIs) such as Femara (Letrzle), Arimidex (Anastrzle), r Exemestane (Armasin). AI s wrk by blcking the enzyme armatase, which cnverts the hrmne andrgen int small amunts f estrgen in the bdy. This means that less estrgen is available t stimulate the grwth f hrmne-receptr-psitive breast cancer cells. Althugh pstmenpausal wmen d nt have varian functin fr prducing estrgen, they still prduce sme estrgen in their adrenal glands and elsewhere, s AIs can be quite effective fr this ppulatin. Letrzle appears t be a mre ptent suppressr f ttal-bdy armatizatin and plasma estrgen levels cmpared with Arimidex, s this shuld be taken int cnsideratin when beginning hrmnal treatment with an AI. Frm: http://www.medscape.rg/viewarticle/434229 AIs may be prescribed alne as a mntherapy, r specifically paired with targeted drugs called Cyclin-Dependent Kinases (CDKs). Targeted drugs act upn genes, prteins r ther substances that cntribute in sme way t the grwth and develpment f cancer cells. Ibrance (Palbciclib), Kisqali (Ribciclib) and Verzeni (Abemaciclib) are CDKs. Patients shuld be warned that, unlike Ibrance and Verzeni, Kisqali has been knwn t cause QT Interval Prlngatin (accelerated heart rate that can lead t lss f cnsciusness, cardiac arrest, r even death) as well as Hepatbiliary Txicity (txicity t the liver, gallbladder, bile ducts, and/r bile). It shuld be nted that Armasin may als specifically be paired with Afinitr, but nly in the secnd-line setting. Fulvestrant (Fasldex) is a Selective Estrgen Dwnregulatr (SERD) which breaks dwn estrgen receptrs n cancer cells. Fulvestrant (Fasldex) may be given alne r paired with Ibrance r Verzeni. The results f a randmized Phase 3 trial indicated that the cmbinatin f Fasldex and Ibrance prvided a prgressin-free survival (PFS) f 9.2 mnths cmpared with 3.8 mnths in the grup taking Fasldex alne, and the results f the Mnarch Phase 2 trial f Fasldex and Verzeni indicated that patients taking bth drugs had a PFS f 16.4 mnths versus 9.3 mnths in the Fasldex-nly grup. Frm: http://www.medpagetday.cm/meetingcverage/asco/51855 and https://seekingalpha.cm/article/4110584-elililly-strives-cunteract-rivals Tamxifen (Nlvadex) r Tremifene (Farestn), which are Selective Estrgen Receptr Mdulatrs, r SERMS. Of these, Tamxifen is the mst cmmnly used fr MBC in the US. SERMs wrk by sitting in the estrgen receptrs in breast cells. If a SERM is in the estrgen receptr, there is n rm fr estrgen and it can't attach t the cell. If estrgen isn't attached t a breast cell, the cell desn't receive estrgen's signals t grw and multiply. Tamxifen is far mre widely used in the US, althugh fr pstmenpausal patients with flaws in their CYP2D6 genetic pathway, Farestn is a better chice than Tamxifen because it des nt rely n this pathway t be effective (mre abut Tamxifen and CYP2D6 under Pssible Causes fr Hrmnal Therapy Resistance in this chapter). A subset f individuals with metastatic breast cancer may experience a "flare" f their breast cancer within tw days t three weeks after starting tamxifen. This may cause an increase in bne pain, a high bld calcium level, and in individuals with breast cancer invlving the skin, an increase in the size and/r number f these skin ndules, r skin redness. These flares usually subside within fur t six weeks. In the meantime, the symptms can be treated with measures that reduce pain and Cpyright 2015 Anne Leser Updated Oct. 2017 Page 14
lwer bld levels f calcium. Frm: http://www.uptdate.cm/cntents/treatment-f-metastatic-breast-cancerbeynd-the-basics Estrgen (Ethinyl Estradil) t re-sensitize breast cancer t hrmnal therapy (this is als smetimes an effective therapy in and f itself) Megace (Megestrl Acetate), is a synthetic prgesterne (Prgestin), which may cunteract sme f the effects f estrgen Haltestin (Fluxymesterne) is an Andrgen drug. Andrgens are male hrmnes. Fr mbc patients, andrgen drugs are used t blck the ability f the pituitary gland t cntrl estrgen prductin. The mst cmmn andrgen drug used is fluxymesterne (Haltestin), which is given rally as a pill. Hrmnal Therapy Sequence fr Pstmenpausal Patients The sequence f prviding hrmnal (endcrine) therapy fr pstmenpausal patients will vary, as much f it depends upn what - if any - hrmnal therapy drugs the patient has previusly taken and hw recently they were administered. The sequence will als depend upn the cuntry in which the patient resides. Generally, there is a chice f prviding single drugs r a cmbinatin f drugs, with cmbinatin drugs generally precipitating mre side effects. A physician at the Eurpean Sciety fr Medical Onclgy (ESMO) 2017 Cngress stated that, "Nw, fr the first time, we have insights suggesting that patients with certain clinical characteristics may benefit differently frm treatment with a CDK 4/6 inhibitr, including the pssibility that sme patients with a gd prgnsis may be able t start n endcrine therapy alne. In such patients, CDK 4/6 inhibitrs culd ptentially be reserved as a next line f treatment fr metastatic disease. This idea warrants further study given ur data. Summarizing the data, it was nted that endcrine therapy naive patients and thse with nn-visceral, lw-vlume disease may be mre likely t d better n armatase inhibitrs alne <initially>, althugh the abslute benefit frm CDK 4/6 inhibitr therapy is likely t be higher fr these patients. Patients are urged t discuss the varius ptins with their dctr and t verify insurance cverage, since it is pssible that sme f the cmbinatin drug regimens listed belw may nt yet be cvered by insurance. The authr has dne her best t piece tgether the recmmended hrmnal therapy sequence pstmenpausal patients in the US, Canada, and Eurpe, althugh patients are encuraged t review this list with their dctr since these guidelines may vary. FOR POSTMENOPAUSAL HORMONE RECEPTOR POSITIVE, HER2 NEGATIVE MBC PATIENTS IN THE US: First line Treatment Optins (depending upn what, if any, recent treatments the patient may have had in the adjuvant setting): * Letrzle alne * Arimidex alne * Armasin alne * Fasldex alne * Letrzle and Ibrance * Letrzle and Kisqali * Arimidex and Ibrance * Arimidex and Kisqali * Armasin and Ibrance * Armasin and Kisqali Secnd line Treatment Optins (depending upn prir treatment): * Letrzle alne * Arimidex alne * Armasin alne * Fasldex alne * Letrzle and Ibrance * Fasldex and Verzeni * Verzeni alne (if the patient already underwent endcrine therapy AND chemtherapy that failed) * Fasldex and Ibrance * Armasin and Afinitr Cpyright 2015 Anne Leser Updated Oct. 2017 Page 15
Third line Treatment Optins (depending upn prir treatments): * Pssibly any f the abve therapies (althugh nt all cmbinatins are widely used in a third-line setting) * Tamxifen r Farestn Furth line Treatment Optins (depending upn prir treatments): * Pssibly any f the abve therapies (althugh nt all cmbinatins are widely used in a furth-line setting) * Either Estradil, Megestrl Acetate (Megace), r Haltestin (Fluxymesterne) FOR POSTMENOPAUSAL HORMONE RECEPTOR POSITIVE, HER2 NEGATIVE MBC PATIENTS IN CANADA: First line Treatment Optins (depending upn what, if any, recent treatments the patient may have had in the adjuvant setting): * Letrzle alne * Arimidex alne * Armasin alne * Letrzle and Ibrance Secnd line Treatment Optins (depending upn prir treatment): * Letrzle alne * Arimidex alne * Armasin alne * Fasldex alne * Fasldex and Ibrance * Armasin and Afinitr (The authr was unable t lcate specific infrmatin abut apprved third and furth line therapies fr Canadian patients, althugh it is likely that Tamxifen wuld be a third line candidate, after which Megace may be a furth line ptin ). FOR POSTMENOPAUSAL HORMONE RECEPTOR POSITIVE, HER2 NEGATIVE MBC PATIENTS IN EUROPE: First line Treatment Optins (depending upn what, if any, recent treatments the patient may have had in the adjuvant setting): * Letrzle alne * Arimidex alne * Armasin alne * Fasldex alne (Except pssibly in the UK, where NICE Guidelines have prvisinally rejected it) * Tamxifen alne * Letrzle and Ibrance * Letrzle and Kisqali * Arimidex and Ibrance * Arimidex and Kisqali * Armasin and Ibrance * Armasin and Kisqali Secnd line Treatment Optins (depending upn prir treatment): * Letrzle alne * Arimidex alne * Armasin alne * Fasldex alne (Except pssibly in the UK, where NICE Guidelines have prvisinally rejected it) * Fasldex and Ibrance (as abve) * Letrzle and Afinitr * Arimidex and Afinitr * Armasin and Afinitr * Tamxifen and Afinitr (The authr was unable t lcate specific infrmatin abut apprved third and furth line therapies fr Eurpean patients, althugh it is likely that Tamxifen wuld be a third line candidate, after which Megace may be a furth line ptin ). Fr pstmenpausal hrmne receptr psitive, HER2 negative mbc patients in Australia, the authr ffers aplgies because it was nt pssible t lcate viable websites regarding specific hrmnal therapy sequence. That said, an mbc patient in Cpyright 2015 Anne Leser Updated Oct. 2017 Page 16
Australia has kindly indicated that Letrzle, Arimidex, Armasin and Tamxifen (as well as a similar drug called Farestn) may be used alne in the first r secnd line setting. Additinally, after failure f Letrzle r Arimidex, Afinitr may be paired with Armasin in the secnd line setting. Ntably, each f these drugs is listed n the Pharmaceutical Benefits Scheme (PBS). (A PBS listing enables patients wh culd benefit frm a specific drug t purchase it fr the cst f a PBS prescriptin fee). It shuld be nted that althugh the Therapeutic Gds Administratin (TGA) apprved the sale f Ibrance in 2017, this drug is nt listed n the PBS. Therefre, as with any available drug that is nt listed n the PBS, Ibrance wuld need t be paid fr by the patient at a cnsiderable price - pssibly thusands f dllars a mnth. (Kisqali, a sister drug t Ibrance, is nt TGAapprved as f 2017). Interestingly, althugh ne website indicated that Fasldex is an ptin fr patients wh have received prir treatment with Tamxifen, Fasldex des nt appear t be listed n the PBS as f 2017. A PBS search by drug name is available at: http://www.pbs.gv.au/pbs/search Due t the relative paucity f available infrmatin, mbc patients in Australia are encuraged t discuss pssible therapies and their assciated cst with their physicians. Single Agent vs. Cmbinatin Hrmnal Therapy: Experts are nt in cmplete agreement regarding which mbc patients shuld be given single agent vs. cmbinatin hrmnal therapy after diagnsis. One schl f thught is t start endcrine therapy alne in newly diagnsed patients with recurrent disease wh are asymptmatic and have a small vlume f disease and wh might have had a lnger DFS (disease-free survival) befre recurrence. These are patients wh may be mre likely t retain endcrine-respnsive disease and culd have a rbust respnse t endcrine therapy alne; therefre, the use f a CDK4/CDK6 inhibitr might be reserved t thse that may nt r d nt shw benefit frm single agent therapy. Sme physicians feel that endcrine therapy alne is a gd strategy fr patients wanting t preserve their quality f life, d nt want t cme in fr frequent bld tests (necessary because f the pssibility f myelsuppressin [a decrease in certain bld cells prduced by the bne marrw], and want t avid ther side effects assciated with Ibrance r Kisqali in first line therapy. That said, ther dctrs feel that in rder t prduce the maximum benefit in metastatic hrmne receptr psitive breast cancer, a cmbinatin f drugs with a CDK4/6 inhibitr such as Ibrance r Kisqali shuld be the first chice. Frm: http://www.medscape.cm/viewarticle/871998#vp_2 Ptential Impact f Being n Afinitr (Everlimus) befre Mving n t Ibrance: Very little research has been undertaken t determine which specific treatments render a patient less likely t respnd t a future treatment. One small study attempted t address this issue in patients wh had previusly taken Everlimus (Afinitr) and then went n a regimen with the CDK4/6 inhibitr Ibrance (Palbciclib). In the small ppulatin in the study (23 patients), the median Prgressin Free Survival (PFS) was 2.9 mnths fr patients wh had previusly taken Afinitr and then mved n t an Ibrance regimen, versus 9.5 mnths fr patients n Ibrance wh had nt previusly been n Afinitr; the clinical benefit rates were 17.4% vs. 66.5% respectively. Since this was a small study, mre effrts are needed t determine whether the use f Afinitr befre Ibrance (r ther CDK4/6 inhibitrs) is definitively assciated with a lw respnse & clinical benefit rate. Frm: http://abstracts.asc.rg/199/abstview_199_183542.html Side Effects f Hrmnal Therapy: Within the first several weeks f hrmne therapy, patients may experience sme bne/jint pain, ht flashes, dizziness, and ther side effects. If a patient feels that that the side effects are becming t challenging t cpe with, they shuld speak with their dctr abut switching t the nn-generic frm f the drug r pssibly switching t anther drug. These patients may als wish t refer t the sectin entitled, Therapies fr Pain and Neurpathy. Tips when Taking Fasldex (Fulvestrant): Fasldex shts are administered in the butt and can be quite uncmfrtable bth during and after the injectins are given, which is due in part t the thickness f the vaccine. Patients have prvided the fllwing tips t mitigate discmfrt: Warm the syringes under yur armpits fr several minutes until the vaccine reaches bdy temperature, which makes the shts easier t administer. Ask the nurse t gently massage the injectin sites befre and after the injectins. Ensure that there is n weight n the area being injected by standing with yur weight n the ppsite ft, r lying dwn n yur stmach and pinting yur tes inward (mst patients prefer this methd). Have the nurse put numbing spray n the area befre injecting the vaccine, and ensure the nurse injects it very slwly (several minutes per site). After the injectin, apply ice packs r heat pads t the area (sme patients drive hme with the car seat heater turned n), drink lts f water, walk as much as pssible, and avid sitting fr lng perids f time. Bne Density Lss: Armatase Inhibitrs may cause a lss f bne density, which leads t higher rates f steprsis and bne fractures cmpared t Tamxifen. Patients wh will begin taking AIs shuld initially have a Bne Density (DEXA) test as a baseline. and repeat the DEXA test every year r tw s that they and their dctr can mnitr any lss in bne density and decide hw t treat it. Sme medicatins may help prevent r slw dwn steprsis, s physicians may prescribe drugs called bisphsphnates r the drug Xgeva t help preserve bne density. In turn, biphsphnates and Xgeva may cause bne, jint and/r muscle pain, s patients with these symptms shuld reprt them t their dctr immediately. In rare cases, a serius jawbne disrder called OsteNecrsis f the Jaw (ONJ) may ccur. If pssible, patients shuld have a dental exam (and infrm their dentist abut their drug plan) befre using a biphsphnate r Xgeva, and have their teeth cleaned every fur mnths while n the drug. Regular exercise can help strengthen and prtect the bnes, as can getting enugh Cpyright 2015 Anne Leser Updated Oct. 2017 Page 17
calcium, Vitamin K2 and Vitamin D. Frm: http://ww5.kmen.rg/breastcancer/armataseinhibitrs.html and http://www.medscape.cm/viewarticle/509074_7 Changes in Hrmne Receptr Status: Breast cancers that are initially ER psitive and/r PR psitive may becme hrmne receptr negative ver time. Likewise, hrmne negative breast cancers can later becme hrmne psitive. (These same principles may als hld true fr HER2). Additinally, if the breast cancer cmes back elsewhere in the bdy, the dctr shuld rder anther bipsy and retest the tissue s hrmnal and HER2 status, because a tumr in ne area f the bdy may have a different hrmnal and/r HER2 prfile frm a tumr elsewhere. Re-trying ( Recycling Thrugh ) Hrmnal Therapies: Patients wh have develped endcrine resistance and have been n chemtherapy may find this f particular interest. At the 2013 San Antni Breast Cancer Sympsium, ne expert frm Dana Farber stated that ne f the mst cmmn suggestins that physicians shuld make fr patients with initially hrmne sensitive MBC wh have had multiple lines f chemtherapy is t revisit the endcrine therapies, even in late stage disease. And he added that this methdlgy is prbably nt being dne with the frequency it deserves. Frm: Page 3 (under Final Clinical Tip ) http://advancedbc.rg/files/sabcs_hal_burstein_n_hr+mbc.pdf Pssible Causes fr Hrmnal Therapy Resistance: Tamxifen Resistance: Fr patients whse dctrs recmmend that they start taking Tamxifen, and fr patients wh are currently taking Tamxifen and nt respnding, a CYP2D6 test may be recmmended. This is because sme peple simply will nt respnd t Tamxifen due t a flaw in their CYP2D6 genetic pathway. Therefre, patients may want t request a CYP2D6 test (using healthy tissue instead f tumr tissue because it appears that test results with healthy tissue are mre accurate). If after taking the CYP2D6 test the patient is fund t have a CYP2D6 flaw, then Farestn, which is a Selective Estrgen Receptr Mdulatr (SERM) similar t Tamxifen, may be a wrthwhile chice fr pstmenpausal (nt premenpausal) wmen.. Frm: http://farestn.cm/hcp/abut/cntinue.html Mutatins in ESR1 (als knwn as ER, a gene that encdes an estrgen receptr prtein), have been shwn t be indicative f resistance t armatase inhibitrs. ESR1 mutatins ccur rarely in primary breast cancer, but have a high prevalence in advanced breast cancers previusly treated with armatase inhibitrs, implying evlutin thrugh selective treatment pressure. (ESR1 mutatins can be identified thrugh bld tests designed t analyze circulating tumr DNA ctdna ). Other Causes f Resistance t Hrmnal Therapy: Researchers are still explring the mechanisms by which breast cancer becmes resistant verall t hrmnal therapy. Upregulatin (an increase in the number f receptrs n the surface f target cells, making the cells mre sensitive t a hrmne r anther agent) f HER2 by either acquisitin f gene amplificatin r verexpressin has been shwn t ccur in sme tumrs, s HER2 may play a driving rle in tumr prgressin by serving as an alternative survival pathway r by reducing the level f ER, thus rendering the tumr less respnsive t estrgen. Preclinical and clinical data suggest the pssibility that tumrs can alternate between ER and HER2 as the dminant pathway, with targeted therapy against ne pathway causing reactivatin f the ther. PR, n the ther hand, is lst mre frequently than ER with hrmnal therapy. With the lss f PR, the tumr becmes mre aggressive and patients have a wrse survival utcme than patients wh maintain PR expressin after resistance t ne endcrine therapy. PR lss might be assciated with increased grwth factr signaling and upregulatin f the PI3K pathway, which decreases PR and ER expressin. Frm: http://www.ncbi.nlm.nih.gv/pmc/articles/pmc3656649/ In sme instances, a patient s hrmne psitive breast cancer is resistant t hrmnal therapy frm the very beginning. These patients may be placed n chemtherapy and/r targeted therapy, and/r explre ther therapies listed herein. In ther cases, patients with hrmne receptr psitive breast cancer will initially respnd t hrmnal therapy and then becme resistant t it ver time (this is referred t as endcrine resistance r prgressin). These patients may then try anther hrmnal therapy as described abve, and then yet anther, until their cancer is cnsidered cmpletely hrmne therapy resistant. When that happens, these patients may be placed n targeted therapy, chemtherapy, and/r explre ther therapies in the bulleted sectins belw. A Prmising Drug t lk fr is Etinstat (SNDX-275 r MS-275): Etinstat (SNDX-275 r MS-275): This drug is belngs t a class f drugs called HDAC (Histne DeACetylase) Inhibitrs. Mutatins f genes that encde HDACs have been linked t tumr develpment, and HDACs may be prmising therapeutic targets fr cancer treatment. The FDA has designated Entinstat as a Breakthrugh Therapy fr the treatment f lcally recurrent r metastatic Estrgen Receptr (ER)-psitive breast cancer when added t Armasin in pstmenpausal wmen whse disease has prgressed fllwing nnsteridal Armatase Inhibitr therapy. (Breakthrugh Therapy Designatin is a frm f Fast Track Designatin, which is meant t facilitate the develpment and review f new drugs intended t treat serius cnditins). In an earlier Phase 2 study called ENCORE 301, (a randmized, placeb-cntrlled Phase 2 study f Armasin with and withut Entinstat) there was imprvement in Overall Cpyright 2015 Anne Leser Updated Oct. 2017 Page 18
Survival fr patients treated with Armasin plus Entinstat. At a median fllw up f 25 mnths, treatment with the cmbinatin resulted in an 8.3 mnth imprvement in Overall Survival, crrespnding t a 41% reductin in the risk f dying. As f January 2016, this drug is als in clinical trials. Frm: http://www.empr.cm/phase-2-trial-update-f-entinstat-fr-metastatic-breast-cancer/article/243134/ and http://www.ascpst.cm/viewnews.aspx?nid=8525 and https://www.clinicaltrials.gv/ct2/shw/nct02453620?term=entinstat+and+metastatic+breast&recr=recruiting&rank= 1 and https://www.clinicaltrials.gv/ct2/shw/nct02115282?term=entinstat+and+metastatic+breast&recr=recruiting&rank= 2 Althugh the abve infrmatin is based upn the verexpressin f Estrgen and/r Prgesterne, the gd news is that many hrmne psitive breast cancers may als have ther types f targets fr treatment. Fr example, 88% f hrmne psitive breast cancers are psitive fr Andrgen Receptrs (AR), which may be treated (in clinical trials) with targeted drugs in much the same way that hrmne psitive breast cancers are treated with hrmnal drugs. Furthermre, up t 23% f hrmne receptr psitive patients have an amplificatin f FGFR1 and/r chrmsme 11q. This is significant because therapies are being develped which specifically target these factrs. Additinal infrmatin abut Andrgen Receptrs and FGFR1/11q is lcated in the sectin entitled Research and Ptentially Helpful Therapies (the last f the bullets mentined belw). Fr additinal infrmatin, suggested sectins include: Persnalized Medicine fr tumr testing and ther ptins Hrmnal Therapy fr a full list f FDA-apprved hrmnal therapy drugs Chemtherapy fr a full list f FDA-apprved chemtherapy drugs Targeted Therapy in which the drug Afinitr is described Research and Ptentially Helpful Therapies fr infrmatin abut experimental and prmising therapies HER2 Psitive Breast Cancer and Related Therapies This sectin applies t patients whse MBC is HER2 receptr psitive, and bth Estrgen Receptr (ER) and Prgesterne Receptr (PR) negative. HER2 (human epidermal grwth factr receptr 2) is a gene that can play a rle in the develpment f breast cancer. Each patient s pathlgy reprt shuld include infrmatin abut HER2 status, which tells the patient whether r nt HER2 is playing a rle in the cancer. The HER2 gene makes HER2 prteins. HER2 prteins are receptrs n breast cells. Nrmally, HER2 receptrs help cntrl hw a healthy breast cell grws, divides, and repairs itself. In abut 25% f breast cancers, the HER2 gene desn't wrk crrectly and makes t many cpies f itself (knwn as HER2 gene amplificatin r being HER2 psitive). HER2-psitive breast cancers tend t grw faster and are mre likely t spread and cme back cmpared t HER2-negative breast cancers. But there are currently many medicines specifically targeting HER2-psitive breast cancers, and as a result it is nt unusual fr patients with HER2+ t have a better prgnsis than thse with ther breast cancer prfiles. Sme breast cancers that are initially HER2 psitive can becme HER2 negative ver time. And if the patient s breast cancer cmes back elsewhere in the bdy, his r her dctr shuld rder anther bipsy and retest the tissue s hrmnal and HER2 status, because a tumr in ne area f the bdy may have a different hrmnal and/r HER2 prfile frm a tumr elsewhere. When determining a HER2+ patient s therapy, dctrs als need t take int accunt where the patient s cancer has spread because there are ften additinal therapies that may be warranted. Specific HER2 + breast cancer treatments, which are ften used in cnjunctin with cyttxic chemtherapy drugs, are: Herceptin (Trastuzumab) Kadcyla (als knwn as TDM-1 r Trastuzumab Emtansine). Perjeta (Pertuzumab) Cpyright 2015 Anne Leser Updated Oct. 2017 Page 19
Tykerb (Lapatinib) Fr HER2+ mbc patients utside the US and Canada, a 2016 study fund that a similar but less expensive experimental drug wrks just as well as the standard drug Herceptin (trastuzumab). Researchers cnducted a randmized Phase 3 clinical trial f the bisimilar trastuzumab antibdy drug MYL-1401O. Their trial included 500 patients in Africa, Asia, Eurpe and Latin America. Patients received chemtherapy and either Herceptin r MYL-1401O fr at least eight cycles, fllwed by Herceptin alne until their disease prgressed. Six mnths later, respnse rates were similar in bth grups, 70% with MYL-1401O and 64% with Herceptin, the study fund. Frm: http://medicalxpress.cm/news/2016-06-cheaper-breast-cancer-drug-clinical.html GUIDELINES FOR HER2 POSITIVE MBC THERAPIES The fllwing drug guidelines fr HER2 Psitive MBC therapies were established by ASCO in 2014: First-line therapy: HER2-targeted therapy is recmmended fr patients with HER2-psitive hrmne receptr negative advanced breast cancer, except fr thse with clinical cngestive heart failure r significantly cmprmised left ventricular ejectin fractin, wh shuld be evaluated n a case-by-case basis. A cmbinatin f Trastuzumab (Herceptin), pertuzumab (Perjeta), and taxane is recmmended fr first-line treatment. Optimal duratin f chemtherapy is at least 4 t 6 mnths r until maximum respnse, depending n txicity and in the absence f prgressin. HER2-targeted therapy can cntinue until time f prgressin r unacceptable txicities. Fr patients with HER2- psitive and estrgen receptr psitive/prgesterne receptr psitive breast cancer, clinicians may recmmend either standard first-line therapy r, fr selected patients, endcrine therapy plus HER2-targeted therapy r endcrine therapy alne. Frm: http://www.institutefrquality.rg/systemic-therapy-patients-advanced-human-epidermal-grwth-factr-receptr- 2%E2%80%93psitive-breast-cancer It shuld be nted that this first-line therapy may be effective even fr patients wh were pre-treated with Herceptin. Frm: http://nclgypr.esm.rg/meeting-resurces/esmo-2014/breast-cancer-metastatic/efficacy-f-anti-her2-retherapy-withtrastuzumab-at-first-relapse-and-r-first-ccurrence-f-metastases-f-her2-psitive-breast-cancer-in-clinical-rutine-4thinterim-analysis-f-the-nn-interventinal-study-nis-ml21589 Ptential fr heart damage: Since Herceptin can cause cngestive heart failure in sme instances, all breast cancer patients wh are candidates fr treatment with Herceptin shuld underg cardiac testing prir t therapy and thereafter be mnitred fr heart damage regardless f age. Frm: http://www.eurekalert.rg/pub_releases/2016-04/uhn-bcp041916.php Additinally, patients wh have hypertensin, are age 50 years r lder, have lw baseline left ventricular ejectin, and/r have been previusly treated with an anthracycline chemtherapy may be mre susceptible t cardiac issues while n Herceptin, and shuld ensure that their nclgist wrks with a cardilgist t determine whether they shuld receive prphylactic (preventive) ACE inhibitrs r beta blckers t prevent r lwer the risk f carditxicity. Frm: CURE Magazine, Octber 2016 T prevent the heart damage caused by chemtherapy, a cardilgist teamed up with a medical nclgist and identified a handful f studies that reprted success using a beta blcker called Carvedill. (Beta blckers slw dwn the heart and lwer bld pressure). They tried Carvedill n abut 50 patients during their chemtherapy treatments. The drug s side effects were minimal and it s an affrdable, generic medicatin. In three years, nne f the patients has any signs f cardiac damage, whereas nrmally a small percentage f patients wuld have already develped heart failure. Anther nclgist stated that Cenzyme Q10 (CQ10) may als affrd sme prtectin fr wmen underging chemtherapies that cmprmise heart functin. It is believed that CQ10 helps t maintain a healthy cardivascular system, and there is evidence f CQ10 deficiency in heart failure. Frm: http://www.thebreastcaresite.cm/chemtherapy/take-heart-smart-treatment-understanding-managing-chem-brain/ Secnd-line therapy shuld be Kadcyla (TDM-1). Kadcyla can cnfer an Overall Survival (OS) f 29.9 mnths when used as a secnd-line therapy, which is superir t Lapatinib (Tykerb) plus Xelda (Capecitabine) which prvided an OS f 25.9 mnths. (Kadcyla can als be a viable first-line therapy in patients fr whm Herceptin, Perjeta and a taxane might be t txic). Frm: http://www.jnccn.rg/cntent/13/12/1475.full and http://am.asc.rg/meeting-n-demand/presentatin/breast-cancermetastatic Third-line therapy: Treatment depends n what patients received as first- and secnd-line therapies. Optins may include Kadcyla, hrmnal therapy r chemtherapy with Herceptin and in sme cases with Tykerb (Lapatinib), the cmbinatin f Herceptin and Tykerb, r a Perjeta-based regimen if the patient has nt received Perjeta befrehand. Frm: http://www.heali.cm/hematlgy-nclgy/practice-management/news/nline/%7b33ca3c9d-e260-4a90-9039-8952f7f09714%7d/asc-issues-guidelines-fr-advanced-her2psitive-breast-cancer Cpyright 2015 Anne Leser Updated Oct. 2017 Page 20
Belw is a slide frm the ASCO 2017 cnference depicting the treatment ptins fr HER2 Psitive Advanced Breast Cancer: Optimal duratin f chemtherapy is at least 4 t 6 mnths r until maximum respnse, depending n txicity and in the absence f prgressin. The ratinale fr adding Perjeta t Herceptin is that a study fund that HER2+ MBC patients wh were given Perjeta n tp f Herceptin and chemtherapy lived 15.7 mnths lnger than thse n Herceptin and chemtherapy alne. That is the lngest extensin t survival ever seen fr a drug studied in metastatic breast cancer! The median Overall Survival (OS) was 56.5 mnths fr thse given Perjeta, Herceptin and chemtherapy against the already impressive 40.8 mnths fr patients taking nly the lder drugs. Lking at the study results a different way, the risk f dying was reduced by 32% fr patients wh received the Perjeta/Herceptin/Chemtherapy regimen cmpared t thse wh gt Herceptin and chemtherapy. While bth Perjeta and Herceptin have side effects, including rash, diarrhea and a ptentially adverse impact n heart functin, using the tw drugs tgether did nt make these issues any wrse. Frm: http://www.reuters.cm/article/2014/09/28/us-health-cancer-rcheiduskcn0hn06r20140928 Fr HER2+ patients wh have received multiple previus lines f therapy, Kadcyla (TDM1) can still be f majr benefit. In the Phase 3 TH3RESA clinical trial, 602 HER2+ pretreated mbc patients were randmly assigned 3.6 milligrams f T-DM1 per kilgram f bdy weight every three weeks, r treatment f physician's chice. After a median fllw-up f 30.5 mnths, the median verall survival was significantly lnger amng the 404 patients assigned T-DM1 cmpared with the 198 patients assigned treatment f physician's chice: 22.7 mnths cmpared with 15.8 mnths. The verall survival benefit was seen regardless f patient age, hrmne-receptr status, visceral invlvement, and number f prir treatment regimens. Frm: http://www.sciencedaily.cm/releases/2015/12/151211124307.htm A quick heads up as f Dec. 2014: The additin Afinitr t Herceptin and Paclitaxel failed t extend Prgressin Free Survival (PFS) in wmen with HER2+ advanced breast cancer, accrding t results f a randmized Phase 3 study presented at the San Antni Breast Cancer Sympsium. Frm: http://www.heali.cm/hematlgy-nclgy/breast-cancer/news/nline/%7bec80ffa4-afb3-47bf-a84b- 94439242bcf3%7D/everlimus-did-nt-extend-pfs-in-HER2psitive-breast-cancer Cautin Regarding CNS Metastasis: Patients with HER2 psitive MBC shuld be especially vigilant abut unusual symptms that may be related t Central Nervus System (CNS) issues such as headache, numbness, speech and/r cgnitive difficulties, blurred visin, etc. because there is an increased risk fr brain metastasis in patients receiving Herceptin. Frm: http://www.medscape.cm/viewarticle/780802 Additinally, HER2+ MBC patients may have an increased verall risk f CNS Cpyright 2015 Anne Leser Updated Oct. 2017 Page 21