Module 8: ER-Positive Metastatic - PowerPoint Presentation

1. Module 8: ER-Positive Metastatic Breast Cancer Elizabeth O’Reilly, MSN, MPH, ANP-BCSara Hurvitz, MD

2. Disclosures for Ms O’ReillyNo financial interests or affiliations to disclose

3. Disclosures for Dr HurvitzSalary: noneRoyalty: noneReceipt of Intellectual Property Rights/Patent Holder: noneConsulting Fees (e.g., advisory boards): noneFees for Non-CME Services Received Directly from a Commercial Interest or their Agents (e.g., speakers’ bureau): noneContracted Research: Amgen, Ambrx, Bayer, BI, Genentech/Roche, GSK, Lilly, Novartis, Dignitana, Pfizer, Merrimack, OBI Pharma, PUMA, Macrogenics, Seattle Genetics, Pieris, Ambryx, Daiichi Sankyo, ImmunomedicsOwnership Interest (stocks, stock options or other ownership interest excluding diversified mutual funds): noneOther: none

4. Approximately how many patients with the following types of cancer have you interacted with over the past year?Type of cancerMedianBreast cancer40Lung cancer35Colorectal cancer30Myelodysplastic syndromes20Multiple myeloma20Chronic lymphocytic leukemia15Pancreatic cancer10Diffuse large B-cell lymphoma10Prostate cancer10Follicular lymphoma7Melanoma6Type of cancerMedianOvarian cancer6Renal cell carcinoma6Hepatocellular carcinoma5Gastric cancer5Acute myeloid leukemia4Hodgkin lymphoma4Urothelial bladder cancer4Endometrial cancer3Cervical cancer2Mantle cell lymphoma2

5. Day in the Life: ER-Positive Breast Cancer 87 F, lumpectomy then endocrine therapy, "I am not worried about this. I have a life to live."87 F, palbociclib/letrozole, maintains sense of humor: "I've lived a good life, so what happens, happens"58 F, anti-estrogen therapy, panic attacks 42 F, palbociclib, overcame a drug addiction and now facing metastatic disease57 F, AI, bipolar with adherence issues58 F, abemaciclib and letrozole, new diagnosis of metastatic breast cancer, overwhelmed26 F, fulvestrant, palbociclib, young patient who reassures and helps older patients

6. Day in the Life: ER-Positive Breast Cancer 70 F, Palbociclib/letrozole  PD  fulvestrant/alpelisib, PIK3CA and BRCA somatic mutations63 F, exemestane  tamoxifen, Hx endometrial ca, BRCA2 mutation positive, Intolerance to AI50 F, fulvestrant/denosumab, socioeconomical issues/lack of insurance caused her to stop treatment before becoming metastatic88 F, palbociclib/letrozole/denosumab, stoic and lives alone41 F, ribociclib, she thought she hurt her back at work but presented with metastatic disease

7. Day in the Life: ER-Positive Breast Cancer 69 F, ribociclib, cares for her young grandchildren76 F, palbociclib, had to go to a nursing home because her husband recently passed away72 F, palbociclib and fulvestrant, positive attitude79 F, anastrozole, retired nurse52 F, palbociclib, always happy, retired school counselor71 F, endocrine therapy, mental health issues66 F, endocrine therapy, caregiving burden

8. Case 3: 48 yo originally with node-positive breast cancer2008: 48 yo woman diagnosed with R sided, invasive ductal carcinoma, grade 2 of 3. ER positive, PR positive, HER2 negative. Neoadjuvant AC/T, then mastectomy with residual cancer measuring 2.7 cm and 1 of 12 axillary LN. Received postmastectomy radiation and then OFS and tamoxifen.2013: Bone-only metastases; started letrozole. Disease largely followed by tumor markers.2015: Progression  fulvestrant and palbociclib.2016: Genomic testing of primary tumor at DFCI  PIK3Ca wildtypeLate 2017: Progression  capecitabine.2019: Progression in bones; no visceral disease  abemaciclib.

9. AbemaciclibFulvestrant +alpelisib

10. Abemaciclib toxicities/dose reductionsDiarrhea — common, greatest 1st month, loperamide and can add alternating diphenoxylate/atropineFatigueNauseaNeutropenia/thrombocytopeniaPneumonitis

11. Cell-free DNA on plasma doneESR1 Y537S mutation PIK3Ca E545K mutationNote: unclear why baseline tumor and subsequent cfDNA testing differ on PIK3Ca

12. Alpelisib toxicitiesInitiated fulvestrant and alpelisib therapyMonitored fasting glucose weekly Patient developed hyperglycemia by week 2 with glucose = 271Added metformin dosed at 500 mg qdHyperglycemia incidence 79% (grade 3 or 4 = 39%), we tell patients to purchase glucometer, measure fasting glucose levels, keep a diary. FPG at least 1/week x first 2 weeks, then monthly, and as clinically indicated. Monitor HbA1c q 3 months.

13. Alpelisib toxicitiesOther toxicities: Rash (onset as early as a few days or delayed as late as 1 year)diarrhea (incidence 58%)N/V and abdominal pain (incidence 45%)stomatitis (incidence 30%)fatigue/weakness (incidence 42%)pneumonitis (incidence 1.8%)

14. Module 8: ER-Positive Breast CancerSara A Hurvitz, MD, FACPAssociate Professor of Medicine

15. What Is Endocrine Therapy? From Where Did It Originate?(Anti)Hormonal Therapy — first kind of “targeted” therapyFirst recognized in the 1890s, by a Scottish surgeon George Beatson. Learned from Scottish farmers that the removal of ovaries from cows alters their ability to lactate.Removed ovaries from 3 women with breast cancer — the breast tumors shrank dramatically, however when repeated on a larger scale in London only 2/3 of the patients responded. Estrogen discovered by Doisy in 1920Estrogen receptor discovered by Elwood Jensen in 1968

16. ER-αEER-αEHormonally Targeted Therapies(60-75% breast cancer is hormonally driven)PI3KAktmTORRASRafMEKMAPKER Target Gene TranscriptionPPEGFRHER2EEER-αEAromatase InhibitorNonsteroidal AIs:Anastrozole LetrozoleSteroidal AI:Exemestane Selective ER Modulators Tamoxifen Toremifene ER Downregulator Fulvestrant CellCycleTranscriptionSilencingBrufsky. Cancer Treat Rev. 2017;59:22. Brufsky. Oncologist. 2018;23:528.Cell cycle regulationDNA replicationCellular differentiationApoptosisAngiogenesisGnRH analogs (leuprolide, goserelin) block production of ovarian estrogen (renders one post-menopausal)SERMs block ERAIs interfere with the peripheral production of estradiol (conversion of fat/testosterone to estrogen)SERDs (e.g. fulvestrant) are pure antagonists (blocker) of ER and downregulate production of ER

17. Osteoporosis riskMusculoskeletalsyndromeCostNeurocognitionSexual functionHyperlipaemiaCardiovascular diseaseDVTStrokeEndometrial cancerHot flashesTAMOXIFENAIPatient historyAIs versus Tamoxifen: benefit/riskPerez EA. Ann Oncol 2007;18(Supp.8):viii26–35

18. A Tale of Two Trial ParticipantsPatient 1Age 49: Stage I left breast cancer ER+/PR+/HER2- s/p bilat mastec, low 21-gene RS, Tamoxifen 4 yWhile on 5th year of adjuvant tamoxifen diagnosed with left chest wall recurrence and bone metastases (Bx: ER+ PR+ HER2-)Undergoes oophorectomyWhat treatment should she receive? Patient 2 56 yo avid golfer develops SOB; imaging shows large mediastinal mass compressing heartMediastinoscopy: Biopsy ER+ PR+ HER2- breast cancer Staging: chest wall and rib metastases and left breast lesionWhat treatment should she receive?

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21. A Tale of Two Trial ParticipantsPatient 1Age 49: Stage I left breast cancer ER+/PR+/HER2- s/p bilat mastec, low 21-gene RS, Tamoxifen 4 yWhile on 5th year of adjuvant tamoxifen diagnosed with left chest wall recurrence and bone metastases (Bx: ER+ PR+ HER2-)Undergoes oophorectomyPatient 2 56 yo avid golfer develops SOB; imaging shows large mediastinal mass compressing heartMediastinoscopy: Biopsy ER+ PR+ HER2- breast cancerStaging: chest wall and rib metastases and left breast lesionBoth are placed on “TRIO-018” Phase Ib study of palbociclib plus letrozole

22. ER-αEER-αECDK4/6 Inhibitors in ER+ Breast CancerPI3KAktmTORRASRafMEKMAPKER Target Gene TranscriptionPPEGFRHER2EEER-αEAromatase InhibitorNonsteroidal AIs:Anastrozole LetrozoleSteroidal AI:Exemestane Selective ER Modulators Tamoxifen Toremifene ER Downregulator Fulvestrant CDK4/6 InhibitorsPalbociclibAbemaciclibRibociclibCellCycleTranscriptionSilencingSlide credit: clinicaloptions.comBrufsky. Cancer Treat Rev. 2017;59:22. Brufsky. Oncologist. 2018;23:528.Cell cycle regulationDNA replicationCellular differentiationApoptosisAngiogenesis

23. CDK4/6 Inhibitors in MBC: First-line Trials TrialRegimenPhaseNORR,* %PFS, MosHR95% CIPALOMA-1[1]Letrozole ± palbociclibII16539 vs 5510.2 vs 20.20.490.22-0.75PALOMA-2[2]Letrozole ± palbociclibIII66644 vs 5514.5 vs 24.80.580.46-0.72MONALEESA-2[3]Letrozole ± ribociclibIII66839 vs 5516.0 vs 25.30.570.46-0.70MONARCH-3[4]NSAI ± abemaciclibIII49344 vs 5914.7 vs NR0.540.41-0.72MONALEESA-7[5]ET + OS ± ribociclibIII67236 vs 5113.0 vs 23.80.550.44-0.69MONALEESA-3[6,7]Fulvestrant ± ribociclibIII36736 vs 5119.2 vs 33.60.580.42-0.80ALL FDA-Approved Indications1. Finn. Lancet Oncol. 2015;16:25-35. 2. Finn. NEJM. 2016;375:1925. 3. Hortobagyi. Ann Oncol. 2018;29:1541. 4. Goetz. J Clin Oncol. 2017;35:3638. 5. Tripathy. Lancet Oncol. 2018;19:904-915. 6. Slamon. J Clin Oncol. 2018;36:2465-472. 7. Slamon J. ESMO 2019 *Patients with measurable disease.

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26. CDK4/6 Inhibitors in Relapsed/Refractory HR+/HER2- MBCTrialRegimenPhase# patientsORR*PFS (months)HR95% CIPALOMA-31,2Fulvestrant +/- palboIII52111% vs 25%4.6 vs 9.520.460.36 to 0.59MONARCH-2Fulvestrant +/- abemaIII66921% vs 48%9.3 vs 16.40.550.45 to 0.68MONALEESA-3Fulvestrant +/- riboIII72529% vs 41%12.8 vs 20.50.590.48 to 0.73MONARCH-1**Abemaciclib monotherapyII13220%6.0----*in subset of pts with measurable dz at baseline**progression on or after prior endo tx; 1-2 lines of chemo for MBCBoth PALOMA-3 and MONARCH-2: ~60% visceral disease; ~20% pre/perimenopausal (received LHRHa)MONARCH-2: No prior met chemo; PALOMA-3: approx. 1/3 with 1 line prior met chemo1. Turner NC, et al. N Engl J Med. 2015;373:209-219; 2. Cristofanilli M, et al. Lancet Oncol. 2016;17:425-439; Sledge GW Jr, et al. J Clin Oncol. 2017;35:2875-2884; Dickler MN et al. Clin Cancer Res. 2017;23:5218-5224; Slamon DJ. J Clin Oncol. 2018 Aug 20;36(24):2465-2472

27. The Survival Data Are In!

28. MONALEESA-7 Overall Survival28Dr Sara HurvitzRibociclib + ETPlacebo + ETEvents/N83/335109/337Median OS, moNot reached40.9HR (95% CI)0.712 (0.535-0.948) P value.00973Kaplan-Meier EstimateRibociclib + ETPlacebo + ET36 months71.9%64.9%42 months70.2% 46.0% ≈ 29% relative reduction in risk of deathThe P value of .00973 crossed the prespecified boundary to claim superior efficacyLandmark AnalysisHurvitz S et al. 2019

29. MONALEESA-3 Overall Survival with Ribociclib plus Fulvestrant in 1st or 2nd line HR+ MBCThe relative reduction in risk of death with RIB was 28% FUL, fulvestrant; HR, hazard ratio; KM, Kaplan-Meier; NR, not reached; OS, overall survival; PBO, placebo; RIB, ribociclib.29RIB + FULPBO + FULEvents/N167/484108/242OS, median (95% CI), moNR (42.5-NR)40.0 (37.0-NR)HR (95% CI)0.724 (0.568-0.924)P value0.00455Landmark AnalysisThe P value of 0.00455 crossed the prespecified boundary to claim superior efficacy (P < 0.01129)KM EstimateRIB + FULPBO + FUL36 months67.0%58.2%42 months57.8%45.9%Overall Survival, %RIB + FULPBO + FUL02040608010048447045444443642841440239738937436534833432630930028723715992411420242233227223218213207199194187184174169159155147141134107643714300024681012141618202224262830323436384042444648No. of patients still at riskPlaceboRibociclibTime, monthsSlamon D et al. ESMO 2019

30. MONARCH 2: Overall Survival with abemaciclib in patients whose disease has progressed on endocrine therapySledge G et al. ESMO 2019

31. Update on Patient 1 (49 yo)Age 49: Stage I left breast cancer ER+/PR+/HER2- s/p bilat mastec, tamoxifen 4 yrAge 53 metastatic breast cancer, has BSO and starts palbociclib/letrozole on phase Ib trial “TRIO-018”Now age 63, has not had progression. Is the longest person on palbociclib + letrozole for MBC in the world. Able to see her daughter’s wedding this past summer.

32. Update on Patient 2 (56 yo)56 yo avid golfer develops SOB; imaging shows large mediastinal mass compressing heartMediastinoscopy: Biopsy ER+ PR+ HER2- breast cancerStaging: chest wall and rib metastases and left breast lesionPlaced on TRIO-018 phase Ib study of palbociclib plus letrozoleAchieves PR on this therapy and remains on study for 46 cycles (3.5 years)Progression of disease in bones at age of 60What therapy do we recommend now?

33. ER-αEER-αEPI3K/AKT/mTOR Signaling Pathway in Resistance to Endocrine Therapy: Data Supporting EverolimusSuppression of classical ER signaling by ET hypothesized to activate PI3K/AKT/mTOR and RAS/RAF/MAPK signaling pathways, thereby promoting ligand-independent activation of ERCrosstalk between ER signaling and growth factor receptor signaling is considered a major mechanism of resistance to ETPI3KAktmTORRASRafMEKMAPKER Target Gene TranscriptionPPEGFRHER2EEER-αECellCycleTranscriptionSilencingSlide credit: clinicaloptions.comBrufsky. Cancer Treat Rev. 2017;59:22. Brufsky. Oncologist. 2018;23:528.mTOR inhibitorEverolimusCell cycle regulationDNA replicationCellular differentiationApoptosisAngiogenesis

34. Slide credit: clinicaloptions.comYardley. Adv Ther. 2013;30:870.Events (Local), n/NMedian PFS (Local), MosMedian PFS (Central), MosEVE + EXE310/4857.811.0PBO + EXE200/2393.24.1 HR: 0.45(P < .0001)HR: 0.38 (P < .0001)Probability of PFS (Local)Mos00.20.40.60.81.00246810121416182022242628Censoring timesEverolimus + Exemestane in AI-refractory MBC: BOLERO-2 Primary Endpoint: Final PFS AnalysisORR at 18 mos: 12.6% with everolimus + exemestane vs 1.7% with placebo + exemestane (P < 0.0001)

35. Kornblum. J Clin Oncol. 2018;36:1556.Fulvestrant plus Everolimus Phase II PrECOG-0102: PFS (Primary Endpoint) Patients,nMedian PFS, MosFULV + EVE6610.3FULV + PBO655.1Proportion Alive and Progression FreeHR : 0.61 (95% CI: 0.40-0.92; stratified log-rank P = .02)Patients at Risk, nFULV + EVEFULV + PBO66650.00.20.40.60.81.006121824Mos412517126410

36. Update on Patient 2 (56 yo)56 yo avid golfer and postal carrier develops SOB; imaging shows large mediastinal mass compressing heartMediastinoscopy: Biopsy ER+ PR+ HER2- breast cancerStaging: chest wall and rib metastases and left breast lesionPlaced on TRIO-018 phase Ib study of palbociclib plus letrozoleAchieves PR on this therapy and remains on study for 46 cycles (3.5 years)Progression of disease in bones at age of 60Placed on 2nd line exemestane/everolimusRemains on this therapy now for almost 7 years (she is now age 67, has retired and golfs every day!)

37. ER-αEER-αEPI3K/AKT/mTOR Signaling Pathway in Resistance to Endocrine Therapy: Data supporting alpelisib in PIK3CAm ER+ MBCSuppression of classical ER signaling by ET hypothesized to activate PI3K/AKT/mTOR and RAS/RAF/MAPK signaling pathways, thereby promoting ligand-independent activation of ERCrosstalk between ER signaling and growth factor receptor signaling is considered a major mechanism of resistance to ETPI3KAktmTORRASRafMEKMAPKER Target Gene TranscriptionPPEGFRHER2EEER-αECellCycleTranscriptionSilencingSlide credit: clinicaloptions.comBrufsky. Cancer Treat Rev. 2017;59:22. Brufsky. Oncologist. 2018;23:528.PI3K Inhibitors AlpelisibTaselisib Cell cycle regulationDNA replicationCellular differentiationApoptosisAngiogenesis

38. Phase III SOLAR-1: Alpelisib + Fulvestrant vs Placebo + Fulvestrant in HR+/HER2- Advanced Breast CancerPIK3CA-Mutant Cohort(n = 341)Alpelisib 300 mg QD PO + Fulvestrant 500 mg IM* (n = 169)Placebo QD PO +Fulvestrant 500 mg IM* (n = 172)Slide credit: clinicaloptions.comPIK3CA-Nonmutant Cohort(n = 231)Alpelisib 300 mg QD PO +Fulvestrant 500 mg IM* (n = 115)Placebo QD PO +Fulvestrant 500 mg IM*(n = 116)Men or postmenopausal women with HR+/HER2- advanced BC with recurrence or progression on/after prior AI, measurable disease or ≥ 1 predominantly lytic bone lesion, ECOG PS 0-1(N = 572)Stratification by presence of liver/lung metastases,prior CDK4/6 inhibitor treatmentPrimary endpoint: PFS (locally assessed) in PIK3CA-mutant cohortSecondary endpoints: OS in PIK3CA-mutant and PIK3CA-nonmutant cohorts, PFS in PIK3CA-nonmutant cohort and PIK3CA mutant–positive ctDNA, ORR/CBR, safetyAndré. NEJM. 2019;380:1929. Andre. ESMO 2018. Abstr LBA3_PR. NCT02437318.*Fulvestrant given on Days 1,15 of 28 in cycle 1, then Day 1 thereafter.

39. SOLAR-1: Locally Assessed PFS in PIK3CA-Mutant CohortAlpelisib + fulvestrant FDA approved 5/2019 for PIK3CA mutated HR+/HER2- MBC (*If plasma test negative, test tumor tissue!)André. NEJM. 2019;380:1929.HR: 0.65 (95% CI: 0.50-0.85; P < .001)Median follow-up: 20.0 mos (range: 10.7-33.3) Alpelisib + FULV(n = 169)Placebo + FULV(n = 172)Median PFS (95% CI)11.0 (7.5-14.5)5.7 (3.7-7.4)12-Mo PFS, %46.332.9Primary endpoint met (1-sidedP ≤ 0.0199)Patients at Risk, nAlpelisib + FULVPlacebo + FULV16917215816714512014111112389113889780957785678266755871546248544150374329392932213020271917141613149535342323210101000Probability of PFSMos00.20.40.60.81.0012345678910111213141516171819202122232425262728293031

40. SummaryCDK4/6 inhibitors have led to substantial PFS and OS benefits in metastatic disease and should be offered to all patients with HR+ MBC in front-line or 2nd-line settingAfter progression on endocrine therapyTest tumor for PIK3CA (ctDNA or tissue)If positive (and not uncontrolled diabetic), alpelisib + endocrine therapyIf negative, everolimus + endocrine therapyEncourage enrollment on clinical trials!

41. Case 1: 49 yo. ER+ MBCOctober 2002. Stage III breast cancer. ER pos, HER2 neg.S/P mastectomy for 5 cm tumor, 4 of 13 axillary nodes positiveAdjuvant AC/paclitaxelPostmastectomy XRTAdjuvant tamoxifen x 5 years, then oophorectomy followed by anastrozole for 5 yearsJune 2015. Work up for nonspecific symptoms showed elevated tumor markers  scans showing bone metastasesL iliac bone biopsy shows carcinoma, ER positive, PR positive, HER2 negativeGenomic sequencing attempted but insufficient tissueBegins zoledronic acid, letrozole and palbociclib

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44. Palbociclib complicated by: Anxiety over tumor markers — results and lack of consistency between labs Isolated neutropenia cycle 1 but remained on full dose

45. Palbociclib dose reductionsNeutropenia: Neutropenia is frequently reported with palbociclib therapy. Grade 3 (57%) or 4 (5%) - CBC day 1 and 14 x 2 cycles and as clinically indicated. - ANC=1000 and platelets=100,000 to treat Fatigue: per patient tolerance

46. Serum tumor markers in breast cancerCEA and CA 15-3 most widely usedNot useful for: Early stage disease-lack of sensitivity/specificity. Mammogram and histopathology are primary modalities for detecting early breast cancer Surveillance after primary breast cancer treatment – not sensitive nor specific for breast cancer relapse. Many patients need reassurance about this. Most useful for monitoring selected patients with metastatic disease per ASCO clinical guidelines look at trends not isolated valuesnonspecificscans are gold standardvariations between labs seen with our patientsKokko R et al Ca 15-3 in the follow up of localized breast cancer: a prospective study. Eur J Cancer 2002; 38:1189; Emens LA et al. The follow up of breast cancer to Guide Decisions on Systemic therapy for Women With Metastatic Breast Cancer:Semin Oncol,2003;30:338; VanPoznak et al. Use of Biomarkers to Guide Decsions on Systemic Therapy for Women with Metastatic Breast CAncer: ASCO Clinical Practice Guidelines. J Clin Oncol 2015:33:2695

47. Spring 2019. Progressive tumor in bones with rising tumor markers.Plasma / cf DNA genomic testing shows wildtype PIK3CaSwitched to fulvestrant and everolimus 10 mg dailyLetrozole +palbociclibFulvestrant + everolimus

48. Managing everolimus toxicities dexamethasone elixir BID 1st cycle to prevent mouth sores diarrhea/nausea pneumonitis — be on lookout for symptoms

49. Special Issues in Oncology Care Professional burnout

50. Professional Burnout AssessmentNeverA few times per yearOnce a monthA few times per monthOnce a weekA few times per weekEvery dayI feel frustrated by my work7%31%13%23%10%12%4%I accomplish many worthwhile things in this job0%4%2%6%4%11%76%