Triple-Negative Breast Cancer

Transcription

1 June 2017 Triple-Negative Breast Cancer Amir Sonnenblick, MD, PhD Sharett institute of oncology Hadassah-Hebrew university medical center, Jerusalem, Israel This presentation is the intellectual property of the author/presenter. Contact for permission to reprint or distribute

2 Case A 63-year-old otherwise healthy woman presents with a 3-cm, ER/PR/HER2-negative, Grade III Metaplastic BC. Origin-Ashkenazi, FH- None

3 MRI R L

4 PET-CT

5 Case-Cont T2N1 TNBC A decision is made to administer neoadjuvant chemotherapy. Would you recommend a platinum agent be included in the treatment regimen? Would you preform BRCA test? 1. Yes 2. Yes if the patient is BRCAg mutation carrier 3. No

6 BRCA germline testing : in all TNBC N = 186 unselected women with TNBC in the Kansas City area are submitted to BRCA (Myriad) testing All comers BRCA mutation frequency 14% 50y 23% 51-60y 12% > 61y 2% Significant Familial Hx (SFHx) 32% If SFHx or age < 50y were the only criteria used one third of mutation carriers would have been missed! No significant Familial Hx 6% P. Sharma, abst 1026, ASCO 2013

7 Probability of Being Alive Responsiveness to Neoadjuvant Conventional Chemotherapy TNBC often responsive to conventional NAC with good outcome similar to other subtypes < pcr = poorer outcome % 94% 88% P =.24 P = % 0.6 pcr/non-tnbc pcr/tnbc 0.5 RD/non-TNBC RD/TNBC Liedtke C, et al. J Clin Oncol. 2008;26: Yrs After Surgery

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9 Pts With DFS (%) GeparSixto: DFS by gbrca Status and Regimen in TNBC BRCA wt PM BRCA wt PMCb BRCA mt PM BRCA mt PMCb BRCA wt PM BRCA wt PMCb BRCA mt PM BRCA mt PMCb Mos von Minckwitz G, et al. SABCS Abstract S

10 Case-Cont BRCA1 185delAG Carrier: Received Neoadjuvant AC taxol carbo with good clinical response Surgery : Lumpectomy SLNB+ clipped node+ ALND Pathology: TNBC, Tumor- Fibrotic tumor bed with residual focus of invasive duct carcinoma, measures 0.9cm. LN 2/14 nodes positive

11 Case-Cont Would you recommend Adjuvant systemic therapy? 1. Capecitabine 2. PARPi 3. Metronomic 4. No (others)

12 What to do with Pt without pcr CREATE-X Stage I-IIIB HER2- BC Non-pCR, post Surgery N = 910 TN 1/3 Capecitabine 2500 g/m²/day PO Days 1-14 Q3W for 8 cycles No Chemo 5y OS 89% 83% P <0.01 Different populations Pharmacogenomics (Asian populations) Use of 5FU in 1/2 ER+ HR 0.81, TN HR 0.58 Masuda, et al. NEJM 2017

13 Exploiting DNA Damage Repair Deficits to Kill Cancer Cells PARP olaparib PARP plays a pivotal role in repairing single strand DNA breaks (SSBs). PARPi traps PARP on SSBs Repair by Homologous Recombination Survival Normal cell Cancer cell with BRCA mutation continuous PARP inhibition leads to CUMULATIVE DNA DAMAGE GENOMIC INSTABILITY AND CELL DEATH Death

14 Flow Chart- Olympia study design BRCA mutation carriers with «high risk» TNBC If residual tumor after neoadj CTX Following adjuvant chemotherapy for node + disease or T > 2cm if node - Randomization Olaparib (300mg daily) X 1year Placebo X 1year

15 Metronomic Chemotherapy International Breast Cancer Study Group (IBCSG) Trial randomized phase III trial 1086, ER/PgR-Negative Breast Cancer following breast cancer surgery and standard induction chemotherapy Randomization 12 months of CM Maintenance chemotherapy (CMM) No CMM CMM- Cyclophosphamide 50/mg/day orally continuously; Methotrexate 2.5 mg/twice a day orally days 1 and 2 of every week for 1 year

16 Case-Cont Received RT adjuvant with no systemic treatment. 3 years later Pt developed lung metastasis Received taxane/platinum + avastin progression Second line: Eribulin + avastin progression Xeloda, Navelbine- progression

17 Case-Cont For a patient with refractory metastatic metaplastic triplenegative breast cancer who wished to receive further treatment, what would you recommend? 1. NGS targeted therapy 2. PARPi 3. Immunotherapy Anti-PD1/PDL1 4. Akt/mTOR inhibitors

18 Randomized (2:1), openlabel, phase 3 HER2- BC Stage 4 2 lines N = 302 TN 1/2 Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation ( OlympiAD) physician s choice Single agent eribulin/navelbine/capecitabine Olaparib monotherapy 300 mg twice daily TN-HR-0.43, ER+ HR 0.82 (NS) Previous platinum -1/3 HR-0.67 AE- 36% Vs 50% (>gr3) OS NS (final when 60% ) PFS 4.2m RR 60% Vs 29% 7m Robson M, et al. NEJM 2017 HR0.58 P <0.001

19 Subtyping of TNBC reveals marked heterogeneity pcr Basal-like 1 ++ Basal-like 2 - Immunomodulatory +(+) Mesenchymal-like +(+) Mesenchymal stem-like Luminal androgenreceptor Unclassified +(+) B. D. Lehmann, J Clin Invest 2011 ± ±

20 Metaplastic breast cancers Metaplastic breast cancers are rare and very aggressive tumors comprising ~1% of all breast cancers (usually TNBC) Median survival of 8 months after the development of metastases. Poor response to systemic therapy

21 Response of metaplastic breast cancer to immunotherapy PDL1-100% TILS Adams, Breast Cancer 2017

22 Metaplastic breast- PDL1

23 metaplastic breast cancer and PI3K/AKT/mTOR Reported responses to PI3K/AKT/mTOR inhibitors PIK3CA (29%), PIK3R1 (11%), ARID1A (11%), FAT1 (11%), and PTEN (11%). This study highlights the genetic basis and the importance of PI3K/AKT/mTOR Wnt signaling in MBCs

24 NGS and EVOC

25 Majumder, Nature Comunications 2015

26 Ex Vivo organ Culture

27 Summary Metaplastic breast cancers are rare and very aggressive tumors Potential role for PI3K/AKT/mTOR inh Potential role for anti-pdl1/pd1. EVOC PARPi in BRCA+