6/13/17. Disclosures. Treating Breast Cancer in People with Mutations. Off Label Use. I will be discussing off label use of medications today.

Transcription

1 Treating Breast Cancer in People with Mutations Steven J. Isakoff, MD, PhD Massachusetts General Hospital Cancer Center June 9, 2017 Disclosures Company ² Myriad Genetics ² AbbVie AbbVie Pharmamar AstraZeneca Genetech/Roche OncoPep Relationship ² Paid Consultant ² Paid Data Safety Monitor Committee Member ² Research Support to Institution Off Label Use I will be discussing off label use of medications today. None of the PARP inhibitors discussed are approved for breast cancer Lurbinectedin (PM1183) is not approved No immunotherapy medications are approved for breast caner 3 1

2 Overview of topics to be covered Breast cancer subtypes and association with BRCA1/2 Triple negative breast cancer BRCA1/2 breast cancer PARP inhibitors Other new treatments Immunotherapy 4 Breast Cancer is more than One Disease Past Breast Cancer Present ER/PR + ER/PR - HER2+ HER2- Future Molecular Subtypes, BRCA-associated Triple negative breast cancer Immunohistochemistry ER PR HER2 High grade ductal ER and PR <1% nuclear with positive normal breast internal control HER2 negative is 0 or 1+ staining or 2+ staining with negative FISH. 2

3 Intrinsic Molecular Subtypes: Basal-like Breast Cancer Luminal A B Basal HER2 About 15% of tumors HER2 Basal Luminal Proliferation Low HER2 cluster expression Low ER (and related genes) cluster expression High basal cluster (CK 5, 17, EGFR, αb crystallin, c- kit etc) expression Very proliferative Sorlie et al, PNAS 2001 Basal-like Tumors are Associated with a Poor Prognosis Sorlie et al, PNAS 2001 Basal-like Guilt by Association: Basal-like Breast Cancer and BRCA1 Intrinsic gene list applied to Van t Veer dataset (Nature 2002) = BRCA1+ = BRCA2+ Sorlie T et al. PNAS 03 Most cancers in BRCA1 mutation carriers are basal-like But Most basal-like breast cancers are not in BRCA1 carriers slide courtesy of Lisa Carey, MD 3

4 Further classification of TNBC: the Vanderbilt TNBC Subtypes Treatment implications of TNBC heterogeneity Basal-like 1 (BL1): Cell cycle proliferation, DNA damage response genes Basal-like 2 (BL2): Growth factor signaling (EGF, MET, Wnt/β-catenin, IGF1R Immunomodulatory (IM) Immune cell and cytokine signaling (overlap with medullary breast cancer gene signature) Mesenchymal (M) Cell Motility and differentiation (Wnt, ALK, TGF- β) Mesenchymal stem-like (MSL) Mesenchymal-like but increased growth factor signaling, low proliferation, enrichment of genes associated with stem cells 10 Luminal Androgen Receptor (LAR) Enriched in hormonally regulated pathways, estrogen receptor signaling, androgen receptor signaling. Shows luminal expression patterns (molecular apocrine carcinomas) Lehmann B, J Clin Invest Jul;121(7): Prognosis for BRCA1/2 carriers Controversy about whether BRCA1/2 carriers have different outcome compared to BRCA wild type A large meta-analysis of 66 studies found no clear difference when adjusted for other factors (van den Broek, 2015 PLoS ONE 10(3)) Recent studies may suggest a better prognosis in some subgroups 11 Prospective Study of Outcomes for Sporadic versus Hereditary Breast Cancer (POSH) 3053 patients from UK Invasive breast cancer 40 yo Tested for BRCA1 and BRCA2 in samples analyzed 379 (14%) had BRCA1 or 2 or both 212 BRCA1 170 BRCA2 Characteristic All (2759) BRCA1+ (212) BRCA2+ (170) Node positive 52% 36% 59% ER+ 67% 27% 83% HER2+ 28% 9% 16% Triple Negative 19% 53% 10% 12 Eccles, SABCS

5 Prospective Study of Outcomes for Sporadic versus Hereditary Breast Cancer (POSH) Overall Survival BRCA+ vs WT (8 yr follow up) No difference Similar results comparing BRCA1 vs WT 13 Eccles, SABCS 2016 Prospective Study of Outcomes for Sporadic versus Hereditary Breast Cancer (POSH) In Triple negative breast cancer (511 cases): 11% difference at 10 years favoring BRCA+ 14 Eccles, SABCS 2016 BRCA1/2 Function makes it a therapeutic target for chemotherapy BRCA1 and 2 play key roles in Double Strand Break repair BRCA1 also is involved in mismatch repair pathways Some chemotherapy agents cause DNA damage 15 5

6 Cisplatin and Breast Cancer Sledge (JCO : ) reported 47% response rate in first line metastatic disease unselected for subtype RR range 42-54% in older studies in first line therapy RR 0-9% in previously treated unselected patients Abandoned for many years because of concerns about toxicity and development of taxanes Interest emerged in early 2000 s in patients with triple negative breast cancer Association of TNBC and BRCA1 Platinum for Neoadjuvant Therapy in Sporadic TNBC and BRCA1 Mutation Carriers Sporadic TNBC > 2cm, Stage II/ III Research Core Biopsy N=28 Garber et al, SABCS 2006; Silver et al, JCO 2010 Cisplatin 75mg/ m 2 q3wks x 4 cycles Assess Responseà Standard Adjuvant Therapy per MD pcr 22% 17 ALLIANCE/CALGB Study evaluating addition of Carboplatin and Bevacizumab in Neoadjuvant Tx for Triple Neg Breast Cancer N=443 ER/PR/HER2- Stage II-IIIB Carboplatin improves pcr 18 Sikov J Clin Oncol :

7 GeparSixto Trial: Neoadjuvant carboplatin for Triple Negative Breast Cancer 315 pts (~53% TNBC) 40% node pos 19 pcr Rates by germline BRCA status and Carboplatin in TNBC gbrca tumors are highly sensitive to chemotherapy Platinum does not add much 20 Is cisplatin better than AC for preoperative therapy for BRCA carriers? Randomized Phase II trial: Neoadjuvant Cisplatin vs AC in Women with Newly Diagnosed Breast Cancer and Germline BRCA Mutations N. Tung, PI 7

8 Schema: INFORM trial N=85 Cisplatin 75 mg/m2 x 4 Eligibility: BRCA1/2 + HER2-neg T> 1.5 cm Research biopsy Surgery Adjuvant Chemo N=85 AC x 4 dd or q 21 days Primary aims: pcr and RCB Secondary aim: biomarkers of response What about in the Advanced Setting? 23 TBCRC009: Single agent Cisplatin or Carboplatin in First or Second Line Therapy for Advanced Triple Negative Breast Cancer Primary Endpoint 1 % (number) (95% Confidence Interval) Overall Response Rate (RR) 25.6 % ( ) Complete Response (CR) 4.7% Partial Response (PR) 3.5% Response Rate by BRCA Mutation Status RR BRCA1/2 positive (N-11) 54.5% ( ) BRCA1/2 Wild Type (N=65) 19.7% ( ) BRCA1/2 Unknown (N=10) 33.3% ( ) BRCA1/2 germline mutation carriers had significantly higher response rate 24 8

9 Metastatic TNBC Trial -- TNT Triple Negative Trial (Tutt, PI) N=376 Triple negative Met or locally adv No prior chemo for MBC (except for anthracycline). BRCA carriers stratified R A N D O M I Z E Docetaxel 100mg/m2 X 6 cycles Carboplatin AUC 6 x 6 cycles Crossover at progression, limit to 6 cycles of therapy. Tutt, SABCS 2014 Triple Negative Trial - Top Line Results 26 TNT BRCA results 27 9

10 TNT BRCA results 28 Is Cisplatin Preferred For The Treatment Of BRCA- Associated or Sporadic TNBC? Platinum is active in early and metastatic TNBC But, no difference observed in the TNT randomized trial Triple negative breast cancer is sensitive to a wide variety of chemotherapeutic agents There is a selective advantage for mutation carriers and may be a good option for BRCA1/2+ advanced breast cancer Unclear if Platinum is better for BRCA1/2+ in early stage disease New Therapies for BRCA1/2 Carriers PARP Inhibitors Late Clinical Development PM01183 Investigational Sapecitabine-Seliciclib Immunotherapy Future Directions 30 10

11 31 NATURE VOL 434: APRIL 2005 PARP Inhibitors Mechanism of Action 1. Single Strand Breaks in DNA Recognized by PARP Cancer Cell able to repair single strand break PARP Cancer Cell treated with PARP inhibitor 2. PARP flags DNA for repair and recruits help, and adds PAR to itself PARP BRCA1/2 BRCA Cancer Cell treated with PARP inhibitor 3. After DNA is fixed, the help is released PARP BRCA1/2 -- Cancer Cell dies 32 PALB2 and other mutations may have similar sensitivity PARP Inhibitors Mechanism of Action 1. Single Strand Breaks in DNA Recognized by PARP Inhibit Catalytic Activity 2. PARP flags DNA for repair and recruits help, and adds PAR to itself 3. After DNA is fixed, the help is released Cancer Cell able to repair single strand break PARP Cancer Cell treated with PARP inhibitor PARP PARP BRCA1/2 PARP trapping BRCA Cancer Cell treated with PARP inhibitor BRCA1/2 -- Cancer Cell dies 33 PALB2 and other mutations may have similar sensitivity 11

12 PARP Inhibitors in development Olaparib (AZD2281) AstraZeneca FDA Approved OvCa, Ph3 breast Veliparib (ABT-888) AbbVie Ph3 in breast Niraparib (MK-4827) Tesaro Ph3 in breast, approved in OvCa Talazoparib (BMN-673) Medivation Ph3 in breast Rucaparib (AG-14699) Clovis Ph2 in breast 34 Clinical Opportunities to Use PARP inhibitors in BRCA1/2 Patients Prevention Combinations Neoadjuvant Adjuvant Monotherapy Metastatic 35 The first Phase II trial in BRCA-deficient advanced breast cancer: Olaparib ITT cohort Overall Response Rate, n (%) Complete Response, n (%) Partial Response, n (%) Stable Disease n (%) Olaparib 400 mg bid (n=27) 11 (41) 1 (4) 10 (37) 12 (44) Olaparib 100 mg bid (n=27) 6 (22) 0 6 (22) 12 (44) 36 Adverse Events: Fatigue grade 1 or 2, 56% grade 3, 15% Nausea grade 1 or 2, 26%, grade 3 11% Median of 3 prior lines of chemotherapy. Tutt, Lancet

13 Single Agent PARP inhibition: FDA Registration Studies for BRCA1/2+ Advanced Breast Cancer gbrca1/brca2 Carriers Advanced anthracycline+taxane resistant breast cancer Olaparib OLYMPIAD NCT (Accrual is complete) Niraparib BRAVO NCT Talazoparib EMBRACA NCT (BMN673) R PARP inhibitor as continuous exposure Physican Choice within Standard of Care options: Capecitabine or Vinorelbine or Eribulin or Gemcitabine Primary endpoint: Progression free survival 37 OLYMPIA RESULTS Hot off the press from ASCO 38 OlympiAD: Phase III trial of olaparib monotherapy versus chemotherapy for patients with HER2-negative metastatic breast cancer and a germline BRCA mutation Presented By Mark Robson at 2017 ASCO Annual Meeting 13

14 OlympiAD study design Presented By Mark Robson at 2017 ASCO Annual Meeting Patient characteristics Presented By Mark Robson at 2017 ASCO Annual Meeting Primary endpoint: progression-free survival by BICR Presented By Mark Robson at 2017 ASCO Annual Meeting 14

15 Time to second progression or death (PFS2) <br />by investigator assessment Presented By Mark Robson at 2017 ASCO Annual Meeting Overall survival (interim analysis; 46% data maturity) Presented By Mark Robson at 2017 ASCO Annual Meeting Objective response by BICR Presented By Mark Robson at 2017 ASCO Annual Meeting 15

16 OlympiAD: Additional findings Compared to standard chemotherapy: Similar activity regardless of prior chemotherapy exposure More effective in Triple Negative than ER+ Similar activity with or without prior platinum chemotherapy Side effects generally similar: Olaparib had more nausea Chemotherapy had more low white count Olaparib had improved Quality of Life 46 Olaparib Based on OlympiAD study, we anticipate Olaparib will get FDA approval for metastatic BRCA1/2 associated breast cancer in This will be the FIRST drug FDA approved specifically for BRCA1/2 breast cancer 47 Phase 1 study of: Cisplatin/Navelbine/Veliparib (300mg BID selected) RR = 57% in BRCA1/2 carriers (31% in non-carriers) CBR 71% in BRCA1/2 carriers 35% of patients had prior platinum Most common AE: Nausea, Fatigue, Platelets, Anemia, Neutrophil PARPi may protect against nephrotoxicity and neuropathy 48 16

17 On the other hand Cisplatin/olaparib Phase 1 study Cisplatin 75mg/m2 Olaparib continuous Not tolerable Olaparib intermittent 50mg BID D1-5 Tolerable Cisplatin 60mg/m2 ORR in BRCA1/2 breast ca = 71% Continuous monotherapy after 6 cycles had durable responses Dose limiting toxicity included Neutropenia, lipase elevation 49 Balmana Annals of Oncology 25: , 2014 BROCADE A randomized phase 2 study comparing carboplatin/taxol to carboplatin/taxol+veliparib or temozolomide+veliparib 50 San Antonio Breast Cancer Symposium, December 6-10, 2016 BROCADE: Study Design MetastaCc breast cancer with BRCA1/2 mutacon 2 lines of chemo No prior placnum N = 290 (86 sites, 20 countries) StraCficaCon factors for randomizacon ER and PgR status (posi,ve or nega,ve) Prior cytotoxic therapy (yes or no) ECOG status (0 1 or 2) 1:1 :1 Veliparib 120 mg D1 7 BID + CarboplaCn AUC 6/ Paclitaxel 175 mg/m 2 Q3W* N = 97 Placebo + CarboplaCn AUC 6/ Paclitaxel 175 mg/m 2 Q3W* N = 99 Veliparib 40 mg D1 7 BID + TMZ 150 to 200 mg/m 2 QD, D1 5 N = 94 *Carbopla,n/Paclitaxel administered on D3, 21- day cycle. 28- day cycle. Pa,ents were treated un,l progression or unmanageable toxicity. If both carbopla,n and paclitaxel or if TMZ was discon,nued, placebo/veliparib was discon,nued. This presenta,on is the intellectual property of the authors/presenter. Contact them at Hyo.Han@moffi:.org for permission to reprint and/or distribute

18 San Antonio Breast Cancer Symposium, December 6-10, 2016 Progression- Free Survival Probability of Progression- Free Survival Placebo + C/P Veliparib + C/P Median PFS, months (95% CI) Placebo + C/P N = ( ) Veliparib + C/P N = ( ) Number at risk Months Since RandomizaCon Placebo + C/P Veliparib + C/P HR ( ) P value * Median (95% CI) PFS, Veliparib + TMZ: 7.4 ( ) months; HR = ( ), P = (SABCS program number: P ) TMZ/Vel was inferior This presenta,on is the intellectual property of the authors/presenter. Contact them at Hyo.Han@moffi:.org for permission to reprint and/or distribute. 52 San Antonio Breast Cancer Symposium, December 6-10, 2016 Tumor Response ORR (CR + PR), n/n, % (95% CI) CBR (week 18 progression- free rate), % (95% CI) DOR, median months, (95% CI) Placebo + C/P N = 98 49/80 (61.3%) ( ) 87.0% ( ) 11.1 ( ) Veliparib + C/P N = 95 56/72 (77.8%)* ( ) 90.7% ( ) 11.7 ( ) ProporCon of PaCents with ORR, % Placebo 49/80 + C/P (95% CI) (61.3%) P = Veliparib 56/72 + C/P (77.8%) *P <0.05 for placebo +C/P vs veliparib + C/P. Tumor assessments were per independent radiology reviewer. ORR, CR, and PR shown represent confirmed responses; these analyses included all pa,ents with measurable disease at baseline. DOR analysis included all pa,ents with an objec,ve response. CBR analysis included all randomized pa,ents who had a deleterious BRCA1/2 muta,on per the core lab. DOR, dura,on of response; PR, par,al response. This presenta,on is the intellectual property of the authors/presenter. Contact them at Hyo.Han@moffi:.org for permission to reprint and/or 53 distribute. San Antonio Breast Cancer Symposium, December 6-10, 2016 Conclusions The addi,on of veliparib to carbopla,n/paclitaxel resulted in trends toward improved PFS and OS, and a significant increase in ORR Final OS analysis will occur when the prespecified number of events is reached Further evalua,on of the efficacy and safety of veliparib with weekly paclitaxel and carbopla,n in pa,ents with BRCA- mutated advanced breast cancer is ongoing in the phase 3 randomized trial BROCADE3 (NCT ) This presenta,on is the intellectual property of the authors/presenter. Contact them at Hyo.Han@moffi:.org for permission to reprint and/or distribute

19 PARP inhibitors: Adjuvant Therapy 55 PARP inhibitors for Early Stage Breast Cancer OLYMPIA study: Currently accruing goal 1320 patients Adjuvant Olaparib Assess for improvement in disease free survival (10 yr f/u) Triple negative breast cancer or high risk ER positive BRCA mutation+ Complete at least 6 cycles of chemotherapy 12 months of olaparib 12 months of placebo 56 Mechanisms of Resistance to PARP inhibitors 57 Reversion of BRCA1/2 Truncated mutations P glycoprotein efflux pumps Stabilization of BRCA1/2 mutant protein Loss of 53BP1 Results in restoration of HR in BRCA1/2 cells Presence of hypomorphic BRCA1/2 Low level expression of BRCA1/2 can be stimulated 19

20 Beyond PARP inhibitors for BRCA1/2 carriers 58 PM Lurbinectedin A novel intravenous chemotherapy 2 nd generation derived from the Sea Squirt Binds to DNA Minor Groove Blocks transcription Causes double strand DNA breaks Related to trabectedin which is approved in Europe and Japan PM1183 BRCA normal BRCA mutation Cell death 59 PM01183 Ongoing Study in BRCA+ Advanced Breast Cancer Group A BRCA1/2 mutation 53 patients Advanced breast cancer 0-3 lines of prior therapy Group B No BRCA1/2 mutation 64 patients (closed early) 60 20

21 PM % Response Rate in Arm A Some >1 year Main side effects: Nausea, anemia, neutropenia, Transaminase increase Current status: Additional 20 patient cohort in prior PARP inhibitor treated patients Phase 3 trial in development 61 Combination of Sapacitabine and Seliciclib Sapacitabine Oral DNA analog that gets inserted into DNA and causes single strand breaks Results in double strand breaks Seliciclib Oral Cyclin Dependent Kinase (CDK) 2,5,7,9 inhibitor Inhibits double strand break repair Seliciclib HO N H N HN N N N Sapacitabine Cancer Cell dies 62 Phase 1 study of Sapacitabine + Seliciclib 22 Non-BRCA carriers 16 BRCA carriers (8 breast, 7 ovary, 1 pancreas) 4 responses (25%, 3PR, 1 CR) 2 stable disease 1 patient on 4 years so far New expansion cohort 20 BRCA1/2 patients 63 Dr. Sara Tolaney, DFCI ASCO

22 Immunotherapy Potential Future Directions for BRCA1/2 treatment How can we harness our own immune system to help treat BRCA1/2 breast cancer? 64 Why doesn t our immune system attack cancer? The Secret Handshake that steps on the breaks. The tumor cell tells the Immune T-cell I am one of you, don t attack! 65 Why doesn t our immune system attack cancer? The Secret Handshake that steps on the breaks. Now we have immunotherapy antibody drugs that prevent the handshake and release the breaks so the immune T cell can attack 66 22

23 Immune cells are often found mixed in with tumor cells, and PDL1 is often found on breast cancer cells Without infiltrating Lymphocytes (T-cells) 67 With infiltrating Lymphocytes (T-cells) Evidence of activity in breast cancer Atezolizumab targets PDL1 In a phase 1 study presented at April 2015 AACR meeting: 54 patients with metastatic triple negative breast cancer 69% had PDL1 on tumors Objective response rate was19% 27% had no progression at 6 months Drugs are well tolerated with fatigue, mild nausea, fever 68 Emens, AACR 2015 Slide 4 Presented By Sylvia Adams at 2017 ASCO Annual Meeting 23

24 Pembrolizumab Antitumor Activity in Previously Treated and Previously Untreated mtnbc Presented By Sylvia Adams at 2017 ASCO Annual Meeting Pembrolizumab Antitumor Activity in Previously Treated and Previously Untreated mtnbc Presented By Sylvia Adams at 2017 ASCO Annual Meeting Immunotherapy for Advanced Breast Cancer Checkpoint inhibitors against PD-1 or PD-L1 are active as single agents, but less so after 1 st line The future of immunotherapy in breast cancer is most likely with combinations Combination with chemotherapy and targeted therapies are underway 72 24

25 Immunotherapy in Pre-operative breast cancer I-SPY 2 TRIAL Schema: HER2- Signatures Presented By Rita Nanda at 2017 ASCO Annual Meeting Immunotherapy in Pre-operative breast cancer Pembrolizumab graduated in all HER2- signatures:<br />Both HR+/HER2- and TN Presented By Rita Nanda at 2017 ASCO Annual Meeting Immunotherapy in Pre-operative breast cancer Pembrolizumab graduated in all HER2- signatures:<br />Both HR+/HER2- and TN Presented By Rita Nanda at 2017 ASCO Annual Meeting 25

26 Immunotherapy and potential future Directions for BRCA1/2 carriers Expression of Immunotherapy Targets in Triple negative breast cancer (Basu et al, ASCO 2014) 10 of 38 Triple Negative breast cancers had PDL1 (28%) But 7 of 7 BRCA1+ patient had PDL1+ expression High expression of PD-L1 in BRCA1+ tumors suggests that anti PD-1/PD-L1 therapy in combination with platinum and/or PARP inhibitors may be a synergistic treatment strategy that warrants further study However,Tung et al (ASCO 2015) showed BRCA1+ have similar PDL1 expression as sporadic TNBC 76 Immunotherapy and PARP inhibitors Biologic rationale: PARPi can increase cell death and inflammation à improved CD8+ T cell infiltration and activation concurrent with immune checkpoint modulators PARPi can increase tumor somatic mutations à neo-antigens that prime anti-tumor CD8+ T cells in the presence of immune checkpoint modulation BRCA1 tumors may have high frequency of PDL1 Veliparib has demonstrated synergy with anti-ctla-4 in BRCA deficient pre-clinical models (Higuchi et al, 22 nd CRI Symposium, 2014) 77 Immunotherapy and PARP inhibitors Clinical Studies TOPACIO Study (KEYNOTE 162) Phase 1/2 Clinical Study of Niraparib in Combination with Pembrolizumab in Patients with Advanced or Metastatic Triple-Negative Breast Cancer and in Patients with Recurrent Ovarian Cancer Phase 2 will enroll 48 Triple negative breast cancer patients No prior progression on platinum allowed Nearly complete 78 26

27 Immunotherapy and PARP inhibitors Clinical Studies MTD durvalumab 1500 mg q 4 weeks and olaparib 300 mg BID Only 2 of 11 patients were breast ca Both were BRCA wt triple negative breast ca 1/11 (8% response) 9/11 (83%) disease control > 4 months Expansion cohort now open in TNBC 79 Lee, ASCO 2016 Novel Prevention Strategies in BRCA Carriers 80 Prevention strategies in BRCA1/2 carriers Preclinical data demonstrates veliparib and olaparib can prevent development of tumors in BRCA1 deficient mice Clinical studies likely will be delayed until longer term safety data Rare association with MDS reported 81 27

28 RANKL inhibitors BRCA1 tumor cell of origin likely a luminal progenitor RANKL signaling is important in mammary hormonal signaling RANKL inhibition attenuates tumor onset in BRCA-def mice BRCA patients treated with denosumab have decreased Ki67 (proliferation) Denosumab may be a chemoprevention strategy in BRCA1 carriers 82 Nolan et al, Nature Medicine June 20, 2016 online BRCA-P : A Breast Cancer Prevention Study in BRCA1/2 International Study by ABCSG (with collaboration from the ALLIANCE, ANZBCTG, Poland, UK, Spain). Double blind Ph3 with denosumab 120 mg subq every 6 months x 5 years BRCA1 and BRCA2 carriers Stratified by BRCA 1 vs 2, menopausal status. Powered to study premenopausal BRCA patients 83 Final Points: A plea for Advocacy and Clinical Trial Participation In other cancers with small populations, targeted therapies have seen rapid approval PARP inhibitors have been slow to become available We need collaboration to do trials and get these drugs where they are most needed to patients! 28

29 85 Key Ongoing/Upcoming Clinical Trials to Consider Prevention BRCA-P Use of Denosumab in BRCA1/2+ patients who have not undergone prophylactic mastectomy Pre-operative chemotherapy INFORM Adjuvant Comparing pathologic complete response rate (pcr) of Cisplatin to Adriamycin/Cytoxan in BRCA1/2+ patient with primary cancer >1.5 cm OlympiA Comparing 1 year of olaparib vs placebo after completing adjuvant/neoadjuvant therapy in BRCA1/2+ patients with node positive or tumor >2cm 86 Key Ongoing/Upcoming Clinical Trials to Consider Advanced Breast Cancer PARP inhibitors EMBRACA, BRAVO PARP monotherapy vs standard chemotherapy, phase 3 BROACDE PARP+Carbo/Taxol vs Carbo/Taxol, phase 3 PM1183 (Lurbinectedin) For BRCA1/2 + who have had prior PARP Immunotherapy Numerous trials ongoing as monotherapy and combinations 87 29

30 Summary and Conclusions We ve covered a lot today BRCA1/2 associated breast cancer has similar prognosis to non- BRCA breast cancer, adjusting for subtype May even be better for TNBC due to chemo sensitivity Platinum-based chemotherapy is clearly active in BRCA1/2 associated breast cancer More active than taxanes in advanced disease Ongoing trials to assess early stage PARP inhibitors are active in BRCA+ breast cancer OlympiAD Phase 3 registration study was positive, hopefully the FDA approval is coming soon Other trials ongoing Immunotherapy is an exciting new approach for early and advanced breast cancer Activity in BRCA mutation subgroups is under study 88 Summary and Conclusions Key areas of investigation for BRCA+ patients Does platinum increase cure rates for early stage disease? How can platinum resistance be overcome? Why are some BRCA positive cancers resistant to PARPi? How does PARPi resistance develop during treatment? Reversion? What novel agents might synergize with PARP inhibitors Are BRCA positive tumors differentially sensitive to immunotherapy? What are the next promising novel therapies beyond PARPi? 89 On a personal note Thank You for your attention and to Sue Friedman the FORCE for all of your important work sisakoff@partners.org 90 30