Breast cancer diagnosis and treatment: an update

Transcription

1 Breast cancer diagnsis and treatment: an update Epidemilgy Breast cancer is the mst cmmn cancer in the UK. 1 There are apprximately 44,600 wmen and 300 men diagnsed each year in the UK. 1 Mre than 12,000 wmen and apprximately 100 men die frm breast cancer in the UK each year, making it the secnd mst cmmn cause f death in wmen after lung cancer. 1 Types f breast cancer An early frm f breast cancer in which there is evidence f cancerus cells within the ducts (ductal cancer in situ) is highly lcalised with n spread t the surrunding breast tissue. 1 If left untreated, hwever, this can develp int invasive ductal breast cancer the cause f arund 70 80% f cases. Similarly, carcinmatus cells can develp in cells lining the lbules, withut spread, but arund 10% f breast cancers are invasive lbular cancers, and these are mre cmmn in wmen aged years but rare in men. Familial breast cancer, accunting fr 5 10% f all cases, is caused by the inheritance f ne f the mutated genes; BRCA1, BRCA2, TP53 r PTEN. 1 Arund twthirds f wmen have hrmne-receptr psitive tumurs, in which endgenus estrgen and prgesterne prmte tumur grwth. 1 Sme cancers test psitive fr human epidermal grwth factr receptr-2 (HER2), which als prmtes cancerus grwth. 1 Inflammatry breast cancer in which cancer cells accumulate in lymph channels and ducts t cause blckage and acute inflammatin, is rare. 1 Paget s disease is assciated with 1 2% f cases. 1 It starts with an eczema-like rash, usually affecting the skin arund ne nipple. In 90% f such cases an underlying mass is present, which can be invasive. 1 Presentatin Breast cancer is mst cmmnly diagnsed by breast screening in asymptmatic wmen r by self-examinatin. Warning signs may include any f the fllwing: 1 change in size, shape r feel f breasts the presence f a new lumpy mass that cannt be mved independently frm verlying skin thickening in ne breast r armpit any puckering, dimpling r redness f the skin changes in the psitin f nipple, nipple inversin, nipple rash r discharge a new ne-sided pain r discmfrt. The NHS Breast Screening prgramme is perhaps ne f the mst successful in Eurpe, saving an estimated 1400 lives each year. 2 The prgramme has cntributed 166 JUNE-AUGUST 2008 PHARMACY IN PRACTICE

2 Onclgy special sectin Table 1. Staging breast cancer 3 Stage I II III IV Descriptin Tumur measures <2cm. Lymph ndes in armpit unaffected. N signs that cancer has spread elsewhere in the bdy. Tumur measures 2 5cm r lymph glands in armpit affected r bth. N signs that cancer has spread further. Tumur measures >5cm and may be attached t surrunding structures such as muscle r skin. Lymph glands are usually affected, but there are n signs that the cancer has spread beynd the breast r lymph glands in the armpit. This is lcally advanced breast cancer that is further divided int stage IIIA, IIIB, IIIC depending n the degree f invlvement with the lymph ndes r surrunding structures. Treatment may differ between each stage. Tumur is f any size, but lymph glands are usually affected and the cancer has spread t ther parts f the bdy. This is secndary r metastatic breast cancer. greatly t imprved early detectin and better treatment. 2 Diagnsis Investigatins are usually undertaken in wmen wh have nticed cncerning changes in their breasts that cause them t cnsult their GP wh, after examining the breasts will refer the patient t hspital r breast clinic fr a full investigatin. This will include a medical histry and breast examinatin t feel fr any enlarged lymph ndes at the base f the neck and armpits. Diagnstic tests include a mammgram, which is useful fr finding early changes in the breasts where it may be difficult t feel a lump in wmen aged 50 years r mre. Fr yunger wmen (particularly <35 years 1 ) an ultrasund is usually preferred, because their breasts are t dense t give a clear view thrugh mammgraphy. 1 Ultrasund hwever, can determine whether the breast lump is slid r a cyst. 1 Subsequently, a bipsy may be taken this may be t sample a few cells thrugh fine needle aspiratin cytlgy r t btain cre tissue frm the lump using a larger needle bipsy and will allw a determinatin f malignancy f the tissue. Further scans may be carried ut such as CT, MRI r PET scans if mre detail is required and t check fr secndaries. 1 An excisin bipsy remves the whle lump fr examinatin. Many wmen diagnsed with breast cancer will have surgery and varius standard bld tests are carried ut as part f a pre-perative screen, including: full bld cunt liver functin tests calcium and alkaline phsphatase urea and electrlytes. Once a diagnsis is made the patient s cancer is staged and graded accrding t its prgressin t help decide which treatment regimen is mst apprpriate. the stage but prduces an idea f hw quickly the cancer may develp and refers t the histlgical type f cancer cell. Staging Stage 0 is ductal carcinma in situ (DCIS) where the cancer cells are cmpletely cntained within the breast ducts and this is almst always curable with treatment. Invasive breast cancer stages prgress frm stage I t stage IV as indicated in Table 1. 3 Grading There are three main grades f breast cancer as shwn in Table 2. 3 Treatment The treatment depends n the stage and grade f cancer (whether this is an early stage lcal tumur, lcally advanced r metastatic), a patient s age, menpausal status, whether the cancer is estrgen-receptr psitive (ER+) r HER2+, previus treatment experience, and their fitness and wishes. 1,4 Systemic treatments shuld be guided by evidence-based guidelines that are reviewed regularly t incrprate current research. Where apprpriate, patients shuld be invited t participate in well-designed clinical trials. 4 In additin t raditherapy; therapeutic ptins are either surgical, pharmaceutical r bth. Karin Sass/ istckpht All patients shuld als be tested fr the presence f estrgen, prgesterne and HER2-psitive cells t see whether targeted therapy might be helpful. Once a diagnsis is made, the patient s cancer is staged and graded accrding t its prgressin t help decide which treatment regimen is mst apprpriate. Stages and grading f breast cancer The stage f breast cancer describes its size and whether it has spread beynd its riginal site. In terms f treating a patient the grade is cnsidered less imprtant than Surgery Surgical treatment is the main curative mdality fr primary breast cancer, where Table 2. Grading breast cancer 3 Grade Descriptin 1 Lw grade. Cancer cells lk similar t the nrmal cells f the breast. They are usually slw t grw and less likely t spread. 2 Mderate/intermediate grade 3 High grade. Tumur cells lk abnrmal. They are mre likely t grw and spread quickly. JUNE-AUGUST 2008 PHARMACY IN PRACTICE 167

3 Onclgy special sectin Table 3. Main agents used in breast cancer and their specific indicatins Drug (Class) Mechanism f actin Cyclphsphamide Interferes with cell replicatin by damaging DNA thrugh alkylatin. (Alkylating drug) Indicatin: Early and metastatic breast cancer Flururacil Pyrimidine antagnist. Uracil analgue that interferes with RNA synthesis. Interferes with DNA (Antimetablite) synthesis by inhibiting thymidylate synthesis. Indicatin: Early and metastatic breast cancer Capecitabine Prdrug f 5-flururacil. (Antimetablite) Indicatin: Cmbined with dcetaxel in preference ver single-agent dcetaxel fr lcally advanced r metastatic breast cancer, in thse where anthracycline-cntaining chemtherapy has failed. 11,12 Mntherapy recmmended by NICE as ptin in lcally advanced r metastatic breast cancer in thse wh have nt had capecitabine cmbinatin therapy and after failure f a taxane and anthracyclinecntaining regimen r where anthracyclines are cntraindicated. 11,13 16 Gemcitabine Pyrimidine antagnist. DNA strand terminatr. Inhibits RNA synthesis by disrupting the (Antimetablite) phsphrylatin f nuclesides. Indicatin: Cmbined with paclitaxel in metastatic breast cancer after relapse with adjuvant/neadjuvant chemtherapy, including an anthracycline unless cntraindicated. 17 Within its licensed indicatin NICE recmmends this cmbinatin as an ptin fr metastatic breast cancer nly when dcetaxel mntherapy r dcetaxel plus capecitabine are als cnsidered apprpriate. 18 Methtrexate Flic acid antagnist. Inhibits dihydrflate reductase (essential fr thymidylate synthesis). (Antimetablite) Indicatin: Cmbined with cyclphsphamide and 5-FU fr primary breast cancer with psitive axillary lymph ndes, adjuvant t radical masectmy. 19 Metastatic breast cancer. 8 Epirubicin Intercalatin with planar ring f DNA t inhibit nucleic acid synthesis and mitsis. (Anthracycline) Indicatin: Adjuvant treatment f early breast cancer cmbined with cyclphsphamide and 5-FU. 20 Dxrubicin DNA tpismerase II inhibitr. (Anthracycline) Indicatin: Cmbined r mntherapy in metastatic breast cancer fr patients with pr perfrmance status. 21 (Used interchangeably with epirubicin. Carditxic s avid in patients with cardiac risk. Anthracycline mntherapy usually reserved fr the frail wh dn t tlerate cmbinatin chemtherapy.) Mitmycin Alkylates and crss-links with DNA disrupting its synthesis. (Anthracycline) Indicatin: Cmbined r mntherapy in metastatic breast cancer. 22,23 Mitxantrne DNA tpismerase II inhibitr. (Anthracenedine) Indicatin: Metastatic breast cancer. 24 Dcetaxel Decreases presence f free tubulin by disrupting micrtubule frmatin. Mittic spindle frmatin is (Taxane inhibited leading t mittic arrest. diperpine) Indicatin: Cmbined with dxrubicin in lcally advanced r metastatic breast cancer. 24 Cmbined with dxrubicin and cyclphsphamide (licensed indicatin) recmmended by NICE as ptin fr adjuvant treatment in perable early nde psitive breast cancer. 25 Mntherapy in lcally advanced r metastatic breast cancer after failure with chemtherapy including an anthracycline and alkylating agent. 26 Cmbined with trastuzumab in metastatic HER2+ breast cancer in wmen wh have nt received chemtherapy, and where anthracycline therapy is inapprpriate. 24,27 Cmbined with capecitabine in lcally advanced r metastatic breast cancer after failure f chemtherapy that includes an anthracycline. 11,27 Paclitaxel Disrupts rganisatin f micrtubule netwrk essential fr mitsis. (Taxane) Indicatin: Adjuvant treatment fr nde psitive breast cancer with an anthracycline and cyclphsphamide. 28 Initial treatment f lcally advanced r metastatic breast cancer with either an anthracycline r trastuzumab. 8 Mntherapy fr metastatic breast cancer unrespnsive t initial anthracycline therapy r where cntraindicated. 28 Within its licensed indicatin, paclitaxel is nt recmmended fr the adjuvant treatment f wmen with early nde-psitive breast cancer. 29 Trastuzumab Antibdy against the prtein HER2. (Humanised Indicatin: Early and metastatic HER2+ breast cancer. 24 NICE recmmends use fr adjuvant treatment mnclnal f early HER2+ breast cancer given at 3-weekly intervals fr a year, r until disease reccurs. Als recantibdy) mmended as an ptin in early breast cancer after surgery, chemtherapy (neadjuvant/adjuvant) and raditherapy. 30 Recmmended and licensed in cmbinatin with paclitaxel r dcetaxel (als ften used with vinrelbine but nt licensed) in metastatic breast cancer when anthracycline therapy is inapprpriate. 8 Mntherapy recmmended if received at least tw chemtherapy regimens fr metastatic breast cancer. Prir chemtherapy must have included an anthracycline and taxane, if apprpriate. Hrmnal therapy shuld als be included in suitable ER+ patients. 8 Licensed with an armatase inhibitr in pstmenpausal wmen with metastatic breast cancer, wh have nt received trastuzumab. 24 Vinrelbine Inhibits tubulin plymerisatin and binds t mittic micrtubules causing mittic arrest. (Vinka alkalid) Indicatin: Advanced breast cancer stage III and IV, relapsing after r refractry t anthracycline chemtherapy. 31 Nt recmmended by NICE as first-line treatment fr advanced breast cancer, but mntherapy recmmended as ne ptin fr secnd-line r subsequent line therapy when anthracycline-based regimens have failed. The present state f evidence des nt allw recmmendatin f the rutine use f vinrelbine cmbinatin therapies, althugh vinrelbine is cmbined with trastuzumab as unlicensed therapy recnstructin shuld be available at surgery. 4 Surgical interventins are generally either: lumpectmy, where small, lcalised tumurs are remved alng with minimal surrunding breast tissue; segmental excisin, which is similar t lumpectmy but mre f the surrunding tissue is remved, and mastectmy in which the whle breast is remved. 1 Raditherapy Raditherapy lwers the risk f cancer recurring, either in the remaining breast tissue r in lymph ndes that are treated. 5 Raditherapy shuld be regarded as standard therapy fr all wmen wh have undergne breast cnserving surgery, and cnsidered fr wmen wh have had a masectmy. 4 Raditherapy may als be given as neadjuvant and adjuvant treatment, r as a sle treatment mdality if surgery is inapprpriate. 4 Pharmaceutical therapies Pharmaceutical agents, which will frm the main fcus f this review, include chem-, hrmnal and targeted therapies. Chemtherapy Chemtherapy invlves using a variety f cyttxic agents t halt tumur grwth and/ r destry grwing cancer cells. Chemtherapy can be given as neadjuvant befre surgery t shrink a tumur t make surgery easier/mre successful, r as adjuvant after surgery t reduce the risk f disease relapse/recurrence, r fr advanced disease as a palliative therapy t treat tumur spread. 1 The main classes f chemtherapies used 168 JUNE-AUGUST 2008 PHARMACY IN PRACTICE

4 Onclgy special sectin Table 4. Cmmn cmbinatins used t treat breast cancer Cmbinatin Evidence CMF: Cyclphsphamide, This traditinal regimen is being replaced with anthracycline regimens Methtrexate, 5-FU which when cmpared t CMF, have shwn increased abslute survival rates frm 69% t 72% and reduced recurrence (12%). 4 This cmbinatin can be used if anthracycline therapy is inapprpriate (e.g. cardiac disease). 24 TAC: Dcetaxel, Dxrubicin, Cyclphsphamide Recmmended as an ptin fr adjuvant treatment with early nde psitive breast cancer. 24,25 Hwever, sequential regimens f anthracyclines fllwed by dcetaxel wuld be preferred because f their high txicity. Epirubicin fllwed Adjuvant chemtherapy shuld include an anthracycline unless cntraby CMF indicated. Epirubicin with CMF is mre effective than CMF alne. 4 FEC: Epirubicin, Anthracycline and cyclphsphamide therapy is the standard initial therapy Cyclphsphamide, fr metastatic breast cancer in wmen wh have nt previusly received 5-FU chemtherapy. 10,24 MMM: Methtrexate, Mitxantrne, Mitmycin MM: Methtrexate, Mitxantrne AC: Dxrubicin, Cyclphsphamide Dcetaxel/Paclitaxel (Taxanes) Taxanes appear t be mre effective than lnger-established regimens using cyclphsphamide, 5-FU and dxrubicin r single-agent dxrubicin fr metastatic breast cancer. They prduce a better respnse rate and lnger remissin with an estimated increase in survival time f 20-25%. 4 Single trastuzumab/ Licensed fr tumurs highly expressive f HER2. Trastuzumab + Paclitaxel cancer. 24 Used alne r after surgery, it delays the develpment f metastases and has been the standard adjuvant hrmnal treatment fr pstmenpausal wmen with early ER+ breast cancer when given fr five years. 35 Adjuvant tamxifen substantially imprves the 10-year survival f wmen with ER+ breast cancer. 36 Armatase inhibitrs fr pstmenpausal wmen AI s, taken daily, inhibit the cnversin f andrgen t estrgen in peripheral tissues. They d nt inhibit varian estrgen synthesis and therefre, are effective nly in pstmenpausal wmen. Their use in early ER+ breast cancer in pstmenpausal wmen has been reviewed previusly in Pharmacy in Practice and readers are referred t this article fr further infrmatin. 37 The AI s anastrzle, exemestane, and letrzle are all licensed as adjuvant therapy fr early ER+ breast cancer fr pstmenpausal wmen. 35 NICE recmmends the fllwing ptins fr early ER+ breast cancer: 35 fr breast cancer are alkylating agents, anthracyclines, antimetablites and taxanes. The main chemtherapeutic agents are listed in Table 3 alngside their indicatins specific t breast cancer and assciated NICE guidance. Cmmn cmbinatin therapies A cmbinatin f chemtherapy agents has been shwn t reduce annual recurrence rates and verall death rates by 28% and 17% respectively. 3 Ply-chemtherapy is therefre favured ver mntherapy, especially in wmen aged less than 50 years and sme f the cmmn cmbinatins used alng with evidence t supprt this is summarised briefly in Table 4. There is insufficient evidence in wmen aged mre than 70 years. 34 Dsing cycles NICE recmmends that adjuvant chemtherapy fr breast cancer shuld cnsist f 4 8 cycles with multiple agents, including an anthracycline (epirubicin/dxrubicin). The ptimum regimen remains unclear and variatins in prescribing habits exist between nclgists. 4 Hrmnal therapies Sterid hrmne-receptr psitive breast cancer can be managed with hrmnal therapy and the main ptins are tamxifen, armatase inhibitrs (AI s) and pituitary dwn-regulatrs. Hrmne antagnists are used in pre-perative r pst-perative breast cancer management, r recurrences. Tamxifen Tamxifen, the estrgen receptr antagnist, is the treatment f chice in premenpausal, perimenpausal and pstmenpausal wmen with metastatic breast Table 5. Armatase inhibitrs and their indicatins AI Indicatin Anastrzle Advanced breast cancer in pstmenpausal wmen Exemestane Anastrzle. Primary adjuvant therapy. Als cnsidered fr wmen wh have already received 2 3 years f adjuvant tamxifen. 38 Exemestane. Recmmended after 2 3 years f initial adjuvant treatment with tamxifen. Letrzle. First-line hrmnal treatment and fr extended hrmne treatment after taking tamxifen. AI s als have a rle in advanced breast cancer where anti-estrgen therapy with tamxifen has failed, as detailed in Table 5. Advanced breast cancer in pstmenpausal wmen whse disease prgressed despite anti-estrgen therapy Letrzle First-line treatment in pstmenpausal wmen with advanced breast cancer. 46,47 Advanced breast cancer in pstmenpausal wmen where tamxifen r ther anti-estrgen therapy has failed Pre-perative therapy in pstmenpausal wmen with lcalised hrmne receptr psitive breast cancer t allw breastcnserving surgery. 52,53 Anastrzle and letrzle are at least as effective as tamxifen fr first-line treatment f metastatic breast cancer in pstmenpausal wmen. Hwever, it is nt knwn whether their benefits persist in the lng term. 24 JUNE-AUGUST 2008 PHARMACY IN PRACTICE 169

5 Onclgy special sectin NICE recmmends adjuvant chemtherapy fr breast cancer shuld cnsist f 4 8 cycles with multiple agents, including an anthracycline. Pituitary dwn-regulatrs Gserelin (Zladex) is the mst cmmnly used pituitary dwn-regulatr. It is a luteinising hrmne releasing hrmne (LHRH) agnist. With chrnic use it inhibits pituitary LH secretin leading t a fall in estrgen and teststerne. Gserelin is licensed fr the management f advanced breast cancer in and pre- and perimenpausal wmen. 54 Targeted therapies This includes the mnclnal antibdies, trastuzumab (Herceptin) and the small mlecule tyrsine kinase inhibitr lapatinib (Tykerb). Trastuzumab, which is licensed fr early and advanced breast cancer, binds with the prtein HER2/neu (als knwn as epidermal grwth factr receptr-2 r erbb2 (Table 3) 8 and thereby blcks its prmtin Table 6. Sme nging clinical trials f tumur grwth. Lapatinib binds t bth HER2/neu receptrs and t epidermal grwth factr receptr-1 (erbb1) in breast tissue. Lapatinib is nw licensed in the UK fr metastatic disease in cmbinatin with capecitabine and is currently underging early clinical trials in adjuvant disease. Trastuzumab was initially recmmended fr use in nly advanced breast cancer by NICE. 8 Because up t 25% f cases may test psitive fr HER2, the absence f a licence in early breast cancer was cntinuusly questined in light f prmising clinical trials. 55,56 This absence caused further cntrversy by the creatin f a pstcde lttery where certain health authrities and hspitals wuld fund the treatment, which fr each patient averages 21,500 PA. 8,30 Cnsequently, final guidance frm NICE was published sn after the licence in early breast cancer was accepted by the regulatry authrities in Future research Numerus clinical trials are underway t evaluate existing and nvel therapeutic Carbplatin and Gemcitabine chemtherapy fr breast cancer resistant t anthracyclines and taxane chemtherapy. Phase II trial. Aims t assess the effectiveness f this cmbinatin as gemcitabine is already used in cmbinatin but carbplatin is nt. 57 TACT2 trial: Cmparing tw weekly and three weekly epirubicin cmbined with either CMF r capecitabine after surgery fr breast cancer. Phase III trial. Aims t assess the efficacy f accelerated treatment with the additin f capecitabine. 57 SOFEA trial: Hrmne therapy fr advanced breast cancer. Phase III trial. Invlves fulvestrant which dwn-regulates estrgen receptrs and is an estrgen antagnist. Aims t assess superirity f fulvestrant vs. anastrzle, fulvestrant vs. placeb and exemestane in advanced breast cancer unrespnsive t AI therapy. 57 TNT trial: Triple Negative breast cancer. Phase III trial. Carbplatin is cmpared t dcetaxel fr metastatic r recurrent lcally advanced ER-, PR- and HER2- breast cancer. 57 ACTION trial: Adjuvant chemtherapy in lder wmen. Phase III trial. Aims t assess adjuvant chemtherapy in wmen aged mre than 70 years, and whether accelerated therapy with GCSF supprt will nt cause undue txicity in this grup. 57 SOFT trial: Suppressin f varian functin. Phase III trial. Aims t assess efficacy f tamxifen alne, tamxifen and varian ablatin, and exemestane and varian ablatin. 57 PERSEPHONE trial: Duratin f trastuzumab. Phase III trial. Aims t assess whether wmen with early breast cancer can safely have trastuzumab fr 6 mnths instead f 12 mnths t help lwer the risk f cardiac damage. 57 ASBO study: Phase II trial. Single-arm trial f pertuzumab (HER2 dimerisatin inhibitr) and trastuzumab in HER2+ metastatic breast cancer. Prmising results recently shw patients whse disease prgressed with trastuzumab benefited with cmbined mnclnal antibdy therapy. This cmbinatin is als being evaluated against chemtherapy in the CLEOPATRA trial. 58 TBP study: Phase III trial. Aims t assess trastuzumab treatment in patients with HER2+ metastatic breast cancer requiring subsequent lines f treatment. Recent results shwed a significant imprvement by cntinuing n trastuzumab in cmbinatin with ral capecitabine cmpared with capecitabine alne. 59 agents r management strategies fr breast cancer. T illustrate the breadth f these studies a selectin f sme f the current clinical trials is given in Table 6. Summary Chemtherapy treatment ptins fr breast cancer ffer a gd degree f chice f single agents r cmbinatins, tailred t the type f cancer and its degree f prgressin. Adjuvant chemtherapy shuld be ffered in 4 8 cycles f multiple-agent chemtherapy, which shuld include anthracyclines. If anthracycline therapy has failed r is cntraindicated, capecitabine is an ptin fr lcally advanced r metastatic breast cancer. Vinrelbine mntherapy r gemcitabine and paclitaxel are ther ptins in metastatic breast cancer. Taxanes are recmmended as an ptin fr advanced breast cancer where initial chemtherapy with anthracyclines has failed. They are nt licensed fr adjuvant treatment in early breast cancer, but are cmbined with trastuzumab in metastatic breast cancer where anthracycline therapy has failed. Trastuzumab is als used as mntherapy in early and metastatic breast cancer. All wmen with hrmne receptrpsitive tumurs shuld be ffered hrmne treatment fr five years after primary therapy. This is likely t invlve tamxifen, r an AI plus varian ablatin r an LHRH agnist fr pre-menpausal wmen. Clinical guidelines n the diagnsis and treatment f early and advanced breast cancer are currently pending frm NICE. The clinical trials mentined in this verview f breast cancer management represent a selectin f the main trials in prgress, which will n dubt cntribute t the evidence base fr the develpment f future breast cancer management strategies. Declaratin f cmpeting interests The authr declares she has n cmpeting interests. Jyti Sd, cmmunity pharmacist (Sainsbury s), Swiss Cttage, Lndn 170 JUNE-AUGUST 2008 PHARMACY IN PRACTICE

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