NIHR Innvatin Observatry Evidence Briefing: Nvember 2017 Alpelisib in cmbinatin with fulvestrant fr advanced HR psitive, HER2-negative breast cancer in men and pstmenpausal wmen NIHRIO (HSRIC) ID: 9191 NICE ID: 9572 LAY SUMMARY Breast cancer, a cancer that develps frm the tissues f the breast, is the mst cmmn cancer in the UK. There are many types f breast cancer and they are ften gruped based n the presence r absence f sme specific types f prteins ( receptrs ) in the cells f the patient. The mst cmmn type f breast cancer are thse that are hrmne receptr psitive (HR+) and human epidermal grwth factr receptr 2 negative (HER2-). The advanced frm f the HR+ and HER2- breast cancer ccurs when the cancer has spread t ther parts f the bdy such as the bnes, brain and liver. Alpelisib is a new drug that is being develped fr patients with the HR+/HER2- type f advanced breast cancer. The drug is being develped t be given in cmbinatin with fulvestrant, a drug that is already in use fr the treatment f advanced breast cancer. Alpelisib targets a very specific enzyme that transmits signals t cells, stpping the grwth and survival f cancer cells. Alpelisib is taken rally while fulvestrant is given by injectin. If apprved, the cmbinatin f bth drugs will ffer additinal treatment ptins fr patients with advanced HR+/HER2- breast cancer that have nt respnded well t ther drugs. This briefing is based n infrmatin available at the time f research and a limited literature search. It is nt intended t be a definitive statement n the safety, efficacy r effectiveness f the health technlgy cvered and shuld nt be used fr cmmercial purpses r cmmissining withut additinal infrmatin. This briefing presents independent research funded by the Natinal Institute fr Health Research (NIHR). The views expressed 1 are thse f the authr and nt necessarily thse f the NHS, the NIHR r the Department f Health.
TARGET GROUP Breast cancer (hrmne receptr-psitive (HR+), human epidermal grwth factr receptr 2 negative (HER2-), advanced, men and pstmenpausal wmen) - first r secnd line; in cmbinatin with fulvestrant TECHNOLOGY DESCRIPTION Alpelisib (BYL719) is a phsphatidylinsitl 3-kinase (PI3K) alpha inhibitr with ptential antineplastic activity. The drug specifically inhibits PI3K alpha isfrm f PI3K. Its bilgical activity crrelates with inhibitin f varius dwnstream signalling cmpnents f the PI3K/AKT signalling pathway. This may result in inhibitin f tumur cell grwth and survival in breast cancer cell lines harburing PIK3CA mutatins. 1,2 Fulvestrant (Fasldex) is a medicatin (hydrxysterid derivative) that acts as an anti-estrgen agent. Specifically, it binds t the estrgen receptr with affinity cmparable t that f estradil and dwn regulates the estrgen receptr prtein in human breast cancer cells (selective estrgen receptr degrader). 3 The develpment f alpelisib in cmbinatin with fulvestrant is under develpment as a treatment f men and pstmenpausal wmen with HR+, HER2- advanced breast cancer whse cancer has prgressed n r after armatase inhibitr treatment. In the phase III clinical trial (SOLAR-1; NCT02437318), alpelisib is administered rally at 300mg nce daily in cmbinatin with fulvestrant (500mg intramuscular injectin n days 1 and 15 f cycle 1 and day 1 f each subsequent cycle). Treatment duratin is nt reprted fr this trial. Alpelisib is currently in clinical trials fr nn-small cell lung cancer (phase II). The cmbinatin f alpelisib with fulvestrant des nt currently have marketing authrisatin in the EU fr any indicatin. Alpelisib als des nt currently have marketing authrisatin in the EU fr any indicatin. Fulvestrant is a marketed drug in the UK/EU, indicated fr the treatment f HR+, metastatic breast cancer in pstmenpausal wmen with disease prgressin fllwing anti-estrgen therapy. It is indicated fr the treatment fr advanced breast cancer, with a distinct and different mde f actin. Fasldex is als indicated in cmbinatin with palbciclib fr the treatment f wmen with HR+, HER2- advanced r metastatic breast cancer whse cancer has prgressed after endcrine therapy, as mntherapy fr expanded use in wmen with HR+, HER2- advanced breast cancer, wh have gne thrugh menpause and have nt received previus endcrine therapy. Fulvestrant is frmulated as injectin slutin fr intramuscular rute f administratin. 3 Fulvestrant is assciated with adverse effects that include; urinary tract infectins, reduced platelet cunt, hypersensitivity reactins, anrexia, headache, ht flushes, venus thrmbemblism, nausea, vmiting, diarrhea, elevated hepatic enzymes (ALT, AST, ALP), elevated bilirubin, rash, jint and musculskeletal pain, back pain, vaginal haemrrhage, asthenia, injectin site reactins, neurpathy peripheral, sciatica. 4 2
INNOVATION and/r ADVANTAGES PI3K AKT mtor is the mst frequently activated pathway in breast cancer. A number f P13K inhibitrs are being develped by pharmaceutical cmpanies, including pan-p13k inhibitrs. Alpelisib is a P13K alpha-selective inhibitr; targeting a single P13K isfrm may allw administratin at therapeutic dses withut being limited by txicities assciated with inhibiting multiple isfrms. 5 If licensed, alpelisib in cmbinatin with fulvestrant will ffer an additinal treatment ptin fr men and pstmenpausal wmen with HR+, HER2- advanced breast cancer whse cancer has prgressed n r after armatase inhibitr treatment. Nvartis Pharmaceuticals. DEVELOPER PATIENT GROUP BACKGROUND Breast cancer arises frm the tissues f the breast and mst cmmnly riginates in the cells that line the ducts. There are several types f breast cancer described accrding t the receptrs expressed n the surface f tumur cells, stage f diagnsis, and rate f grwth. 6 HR+ breast cancer includes disease in which tumur cells express either estrgen receptrs (ER+) r prgesterne receptrs (PR+). 7 Apprximately 80% f breast cancers in pstmenpausal wmen are HR+ and arund tw thirds f breast cancers are ER+. Human epidermal grwth factr receptr 2 (HER2) is a member f the epidermal grwth factr receptr family having tyrsine kinase activity. 8 HER2 are verexpressed in arund 15 25% f wmen with breast cancer and prmte tumur grwth. 9 HER2 negative (HER2-) breast cancer refers t disease that des nt verexpress HER2. 7 Advanced r metastatic (stage IV) breast cancer refers t disease that has spread t ther parts f the bdy. Cmmn sites fr metastases include the bnes, liver, lung and brain. The causes f breast cancer are nt cmpletely understd, hwever a number f factrs are knwn t increase its likelihd, such as expsure t radiatin, increased alchl cnsumptin, being taller, being verweight r bese, expsure t estrgen and hrmne replacement therapy, greater breast tissue density, and genetic factrs. The risk f develping breast cancer is als knwn t increase markedly with inheritance f certain genes (e.g. BRCA2, BRCA1 and TP53). 10 Breast cancer in adults can ccur at any age, thugh there is an increased risk in pstmenpausal wmen, and a previus benign breast lump r diagnsis f early breast cancer further increases the risk. Breast cancer is nrmally characterised by a lump r thickened tissue in the breast area, hwever nt all lumps will be cancerus. Other features include a change in breast size r shape, discharge frm the nipple (which may include bld), lumps/swelling in armpits, dimples n the skin f the breast and a rash arund the nipple area. Symptms include pain in the breast r axilla and signs and symptms can ccur in ne r bth breasts. 11 Breast cancer patients experience physical symptms and psychscial distress that adversely affect their quality f life (QOL). Treatment, including chemtherapy, can cause physical and psychlgical prblems that adversely affect patient QOL, and cancer can have ther effects including anger, grief, suffering and pain. 12 3
CLINICAL NEED and BURDEN OF DISEASE Breast cancer is the mst cmmn cancer in the UK, accunting fr 15% f all newly diagnsed cancers. 13 Breast cancer risk is strngly related t age, with almst half (48%) f breast cancer cases in the UK each year being diagnsed in peple aged 65 and ver (2012-2014). Incidence rates fr breast cancer are prjected t rise by 2% in the UK between 2014 and 2035, t 210 cases per 100,000 females by 2035. 14 Mre than 1 in 10 breast cancer cases are diagnsed at an advanced r metastatic stage in the UK. Apprximately 5% f patients present with metastatic breast cancer, and arund 30% f peple wh present with lcalised disease will later develp metastases. Apprximately 70 80% f peple with metastatic breast cancer have HER2- tumurs, f which abut 50% will als be HR+. 14,15 The hrmne receptr status f the breast cancer affects prgnsis. HR+ breast cancers have higher rates f survival cmpared t HR negative breast cancers (breast cancer cells which d nt verexpress estrgen r prgesterne receptrs) at 5 years after diagnsis (1989 t 2004) at 85% vs. 69% respectively. 16 In England in 2015 there were 46,083 registratins f newly diagnsed cancer f the breast (ICD-10 cde C50), and the directly age-standardised rate per 100,000 ppulatin was 1.4 fr males and 170.2 fr females. There were 9,626 registratins f death frm neplasm f the breast, and the directly age-standardised rate per 100,000 ppulatin was 0.3 fr males and 34.3 fr females. 17 In England in 2016/17 there were 207,043 finished cnsultant episdes (FCEs) and 85,801 FCE bed days with primary diagnsis f ICD-10 cde C50 (malignant neplasm f breast). There were 203,454 hspital admissins, f which 169,800 were day cases. 18 The ppulatin likely t be eligible t receive alpelisib in cmbinatin with fulvestrant culd nt be estimated frm available published surces. PATIENT PATHWAY RELEVANT GUIDANCE NICE GUIDANCE NICE technlgy appraisal in develpment. Eribulin fr treating lcally advanced r metastatic breast cancer after ne prir chemtherapy regimen [ID1072] (GID-TA10094). Expected publicatin date t be cnfirmed. NICE technlgy appraisal in develpment. Ribciclib fr breast cancer [ID1026] (GID-TA10141). Expected publicatin date t be cnfirmed. NICE technlgy appraisal in develpment. Breast cancer (HER2 negative, HR psitive) - Everlimus (with exemestane, after endcrine therapy) [ID965] (GID-TA10028). Expected publicatin date t be cnfirmed. NICE technlgy appraisal in develpment. Palbciclib fr treating hrmne-receptr psitive, HER2-negative breast cancer [ID916] (GID-TA10095). Expected publicatin date t be cnfirmed. NICE technlgy appraisal in develpment. Breast cancer (hrmne-receptr psitive, HER2- negative) - palbciclib [ID915] (GID-TA10068). Expected publicatin date t be cnfirmed. NICE technlgy appraisal in develpment. Breast cancer (brain metastases) - etirintecan pegl [ID881] (GID-TA10066). Expected publicatin date t be cnfirmed. 4
NICE technlgy appraisal in develpment. Breast cancer (HER2psitive, metastatic) - pertuzumab (with trastuzumab and dcetaxel) [ID523] (GID-TAG322). Expected publicatin date t be cnfirmed. NICE technlgy appraisal in develpment. Fulvestrant fr untreated hrmne-receptr psitive metastatic breast cancer [ID951] (GID-TA10106). Expected publicatin date: January 2018. NICE technlgy appraisal. Pertuzumab fr the neadjuvant treatment f HER2-psitive breast cancer (TA424). December 2016. NICE technlgy appraisal. Eribulin fr treating lcally advanced r metastatic breast cancer after 2 r mre chemtherapy regimens (TA423). December 2016. NICE technlgy appraisal. Everlimus with exemestane fr treating advanced breast cancer after endcrine therapy (TA421). December 2016. NICE technlgy appraisal. Bevacizumab in cmbinatin with capecitabine fr the first-line treatment f metastatic breast cancer (TA263). August 2012. NICE technlgy appraisal. Fulvestrant fr the treatment f lcally advanced r metastatic breast cancer (TA239). December 2011. NICE technlgy appraisal. Bevacizumab in cmbinatin with a taxane fr the first-line treatment f metastatic breast cancer (TA214). February 2011. NICE technlgy appraisal. Gemcitabine fr the treatment f metastatic breast cancer (TA116). January 2007. NICE technlgy appraisal. Guidance n the use f trastuzumab fr the treatment f advanced breast cancer (TA34). March 2002. NICE Clinical Guideline. Advanced breast cancer: diagnsis and treatment (CG81). February 2009. Last Updated July 2014. NHS ENGLAND and POLICY GUIDANCE NHS England. 2013/14 NHS Standard Cntract fr Cancer: Chemtherapy (Adult). B15/S/a. NHS England. 2013/14 NHS Standard Cntract fr Cancer: Raditherapy (All Ages). B01/S/a. OTHER GUIDANCE Natinal Cmprehensive Cancer Netwrk. Clinical Practice Guidelines in Onclgy (NCCN Guidelines): Breast Cancer. Versin 2.2017 April 2017. 19 Cards F, Csta A, Nrtn L et al. ESO-ESMO 2nd internatinal cnsensus guidelines fr advanced breast cancer (ABC2). The Breast 23(5), Oct 2014. P 489-502. 20 CURRENT TREATMENT OPTIONS The aim f treatment fr lcally advanced r metastatic breast cancer is t cntrl and slw dwn the spread f the cancer, relieve symptms and give the patient the best quality f life fr as lng as pssible. A number f treatment ptins exist. The mst apprpriate treatment will depend n factrs such as where the breast cancer is in the bdy, hw extensive it is (hw many sites and hw large), symptms, previus treatments, the characteristics f the cancer (such as estrgen receptrs) and general health (and any ther medical cnditins) f the patient. 21 NICE guidelines fr managing HR+, HER2- advanced breast cancer recmmend the fllwing treatments. 5
Endcrine therapy r chemtherapy: Offer endcrine therapy as a first-line treatment fr the majrity f patients with HR+ advanced breast cancer. Offer chemtherapy as first-line treatment fr patients with HR+ advanced breast cancer whse disease is imminently life-threatening r requires early relief f symptms because f significant visceral rgan invlvement, prviding they understand and are prepared t accept the txicity. Fr patients with HR+ advanced breast cancer wh have been treated with chemtherapy as their first-line treatment, ffer endcrine therapy fllwing the cmpletin f chemtherapy. Endcrine therapy: Offer an armatase inhibitr (either nn-steridal r steridal) t: pstmenpausal wmen with ER-psitive breast cancer and n prir histry f endcrine therapy pstmenpausal wmen with ER-psitive breast cancer previusly treated with tamxifen. Offer tamxifen and varian suppressin as first-line treatment t premenpausal and perimenpausal wmen with ER-psitive advanced breast cancer nt previusly treated with tamxifen. Offer varian suppressin t premenpausal and perimenpausal wmen wh have previusly been treated with tamxifen and then experience disease prgressin. Offer tamxifen as first-line treatment t men with HR+ advanced breast cancer. Chemtherapy: On disease prgressin, ffer systemic sequential therapy t the majrity f patients with advanced breast cancer wh have decided t be treated with chemtherapy. Cnsider using cmbinatin chemtherapy t treat patients with advanced breast cancer fr whm a greater prbability f respnse is imprtant and wh understand and are likely t tlerate the additinal txicity. Fr patients with advanced breast cancer wh are nt suitable fr anthracyclines (because they are cntraindicated r because f prir anthracycline treatment either in the adjuvant r metastatic setting), systemic chemtherapy shuld be ffered in the fllwing sequence first line: single-agent dcetaxel secnd line: single-agent vinrelbine r capecitabine third line: single-agent capecitabine r vinrelbine (whichever was nt used as secnd-line treatment). Other secnd-line treatments: Everlimus: Everlimus, in cmbinatin with exemestane, is recmmended within its marketing authrisatin, as an ptin fr treating advanced HR+, HER2- breast cancer in pstmenpausal wmen withut symptmatic visceral disease that has recurred r prgressed after a nn-steridal armatase inhibitr. Everlimus is recmmended nly if the cmpany prvides it with the discunt agreed in the patient access scheme. Fulvestrant: Fulvestrant is nt recmmended within its licensed indicatin, as an alternative t armatase inhibitrs fr the treatment f estrgen-receptr-psitive, lcally advanced r metastatic breast cancer in pstmenpausal wmen whse cancer has relapsed n r after 6
adjuvant anti-estrgen therapy, r wh have disease prgressin n anti-estrgen therapy. Pst-menpausal wmen currently receiving fulvestrant within its licensed indicatin as an alternative t armatase inhibitrs fr the treatment f estrgen-receptr-psitive, lcally advanced r metastatic breast cancer whse cancer has relapsed n r after adjuvant antiestrgen therapy, r wh have disease prgressin n anti-estrgen therapy, shuld have the ptin t cntinue treatment until they and their clinicians cnsider it apprpriate t stp. Other third-line treatments: Eribulin: Eribulin is recmmended as an ptin fr treating lcally advanced r metastatic breast cancer in adults, nly when: it has prgressed after at least 2 chemtherapy regimens (which may include an anthracycline r a taxane, and capecitabine) the cmpany prvides eribulin with the discunt agreed in the patient access scheme. This guidance is nt intended t affect the psitin f patients whse treatment with eribulin was started within the NHS befre this guidance was published. Treatment f thse patients may cntinue withut change t whatever funding arrangements were in place fr them befre this guidance was published until they and their NHS clinician cnsider it apprpriate t stp. 22 EFFICACY and SAFETY Trial Spnsr Status Surce f Infrmatin Lcatin Design Participants Schedule Fllw-up Primary Outcmes Secndary Outcmes SOLAR-1, NCT02437318, EudraCT-2015-000340-42); alpelisib vs placeb, bth in cmbinatin with fulvestrant; phase III Nvartis Pharmaceuticals Onging Trial registry 23 EU (incl UK), USA, Canada and ther cuntries Randmised, placeb-cntrlled N=571 (planned); aged 18 years; men and pstmenpausal wmen; breast cancer; hrmne receptr psitive, HER2-negative; advanced; prgressin n r after armatase inhibitr treatment. Randmised t alpelisib 300mg rally nce daily; r placeb 300mg rally nce daily; bth in cmbinatin with fulvestrant 500mg intramuscular injectin n days 1 and 15 f cycle 1 and day 1 f each subsequent 28-day cycle. Fllw-up fr 59 mths Prgressin-free survival (PFS) fr patients with PIK3CA mutant status as per RECIST 1.1 Overall survival (OS) fr patients with PI3KCA mutant status (up t apprx. 59 mths) Overall respnse rate (ORR) (up t apprx. 36 mths) Time t definitive deteriratin f ECOG perfrmance status (up t apprx. 36 mths) Safety and tlerability f alpelisib in cmbinatin with fulvestrant (up t apprx. 37 mths) 7
Key Results - Time t 10% deteriratin in glbal health status/qol scale scre f EORTC QLQ-C30 (up t apprx. 36 mths) Plasma cncentratin-time prfile f alpelisib given in cmbinatin with fulvestrant and apprpriate pharmackinetics parameters (days 8 and 15 f cycle 1, then day 1 f cycles 2,4,6,8) PFS based n radilgy assessments and using RECIST 1.1 criteria (baseline, up t apprx. 36 mths) Clinical benefit rate (CBR) (up t apprx. 36 mths) Change in glbal health status/qol scale scre f EORTC QLQ-C30 (baseline, up t apprx. 36 mths) Summary statistics f fulvestrant and alpelisib plasma cncentratins (days 8 and 15 f cycle 1, then day 1 f cycles 2,4,6,8) PFS fr patients with PIK3CA nn-mutant status (up t apprx. 36 mths) OS fr patients with PIK3CA nn-mutant status (up t apprx. 59 mths) Adverse effects (AEs) Expected reprting date - Estimated primary cmpletin date reprted as Jan 2018. Trial Spnsr Status Surce f Infrmatin Lcatin Design Participants Schedule Fllw-up Primary Outcmes Secndary Outcmes BYLieve, NCT03056755, EudraCT-2016-004586-67); alpelisib in cmbinatin with fulvestrant r letrzle; phase II Nvartis Pharmaceuticals Onging Trial registry 24 EU (incl UK), USA, Canada and ther cuntries Nn-randmised, uncntrlled N=160 (planned); aged 18 years; breast cancer; hrmne receptr psitive, HER2-negative, PIK3CA mutatins; advanced; prgressin n r after CDK 4/6 treatment with an armatase inhibitr r fulvestrant. Patients wh received any CDK 4/6 inhibitr plus armatase inhibitr as treatment (immediately prir) will receive alpelisib 300mg rally nce daily and fulvestrant 500mg intramuscular injectin n days 1 and 15 f cycle 1 and day 1 f each subsequent cycle. Patients wh received any CDK 4/6 inhibitr plus fulvestrant as treatment (immediately prir) will receive alpelisib 300mg rally nce daily and letrzle 2.5mg rally nce daily. Fllw-up fr 25 mths The percentage f patients wh are alive withut disease prgressin as per RECIST (timeframe: date f first dse t apprx. 6 mths) Prgressin-free survival (PFS) fr each chrt PFS n next line treatment fr each chrt Percentage f participants verall respnse rate (ORR) fr each chrt 8
Key Results - Percentage f participants with clinical benefit rate (CBR) fr each chrt Duratin f respnse (DOR) Adverse effects (AEs) Expected reprting date - Estimated primary cmpletin date reprted as Jan 2020. The cst f alpelisib is nt yet knwn. ESTIMATED COST and IMPACT COST Fulvestrant (Falsdex) is marketed in the UK fr the treatment f estrgen-receptr-psitive metastatic r lcally advanced breast cancer in pstmenpausal wmen in whm disease prgresses r relapses while n, r after, ther anti-estrgen therapy. The NHS indicative price fr 2 pre-filled dispsable injectin f fulvestrant (Fasldex) 250mg/5ml slutin is 522.41. 25 IMPACT SPECULATIVE IMPACT ON PATIENTS AND CARERS Reduced mrtality/increased length f survival Reduced symptms r disability Other N impact identified IMPACT ON HEALTH and SOCIAL CARE SERVICES Increased use f existing services Decreased use f existing services Re-rganisatin f existing services Need fr new services Other Nne identified IMPACT ON COSTS and OTHER RESOURCE USE Increased drug treatment csts Reduced drug treatment csts 9
Other increase in csts Other reductin in csts Other: uncertain unit cst cmpared t existing treatments Nne identified OTHER ISSUES Clinical uncertainty r ther research questin identified Nne identified REFERENCES 1 GlbalData. Alpelisib. Available frm: https://pharma.glbaldata.cm/prductsview.aspx?prducttype=0,1&prductid=79984 [Accessed 24 Octber 2017]. Lgin required 2 Natinal Cancer Institute. NCI Drug Dictinary: alpelisib. Available frm: https://www.cancer.gv/publicatins/dictinaries/cancer-drug?cdrid=687431 [Accessed 25 Octber 2017] 3 GlbalData. Fulvestrant. Available frm: https://pharma.glbaldata.cm/prductsview.aspx?prducttype=0,1&prductid=5106 [Accessed 24 Octber 2017]. Lgin required 4 emc. SPC: Fasldex 250 mg slutin fr injectin. 2017. Available frm: https://www.medicines.rg.uk/emc/medicine/14381 [Accessed 09 August 2017] 5 Massacesi C, Tmas E, Urban P et al. P13K inhibitrs as new cancer therapeutics: implicatins fr clinical trial design. Onc Targets and Therapy. 2016;9:203-210. Available frm: https://www.ncbi.nlm.nih.gv/pmc/articles/pmc4708174/ [Accessed 25 Octber 2017] 6 Breast Cancer Care. Breast cancer facts. Available frm http://www.breastcancercare.rg.uk/breastcancerinfrmatin/abut breast cancer/breast cancer facts [Accessed 21st April 2017]. 7 Natinal Institute fr Health and Clinical Excellence. Lapatinib r trastuzumab in cmbinatin with an armatase inhibitr fr the first line treatment f metastatic hrmne receptr psitive breast cancer that verexpresses HER2. Technlgy appraisal TA257. Lndn: NICE; June 2012. 8 Nida Iqbal and Naveed Iqbal. 2014. Human Epidermal Grwth Factr Receptr 2 (HER2) in Cancers: Overexpressin and Therapeutic Implicatins, Mlecular Bilgy Internatinal, vl. 2014, Article ID 852748, 9 p. di:10.1155/2014/852748 9 Macmillan Cancer Supprt. HER2 psitive breast cancer. Available frm http://www.macmillan.rg.uk/cancerinfrmatin/cancertypes/breast/abutbreastcancer/typesandrelatedcn ditins/her2%20psitive.aspx [Accessed 21 April 2017]. 10 NHS chices. Breast Cancer (female) Causes. August 2014. Available frm http://www.nhs.uk/cnditins/cancer f the breast female/pages/causes.aspx [Accessed 21 April 2017] 11 Reinert T, Barris CH. Optimal management f hrmne receptr psitive metastatic breast cancer in 2016. Therapeutic advances in medical nclgy.2015 Nv;7(6):304 320. Available frm https://www.ncbi.nlm.nih.gv/pmc/articles/pmc4622303/ [Accessed 8 August 2017] 12 Perry S, Kwalski TL and Chang C-H. Quality f life assessment in wmen with breast cancer: benefits, acceptability and utilizatin. Health and Quality f Life Outcmes. 2007;5:24. 13 Cancer Research UK. Abut Breast Cancer. 2015; Available frm: http://www.cancerresearchuk.rg/abutcancer/breast-cancer/abut [Accessed 10 August 2017] 10
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