Overview of peculiarities and therapeutic options for patients with breast cancer and a BRCA germline mutation

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3 Overview of peculiarities and therapeutic options for patients with breast cancer and a BRCA germline mutation Dr Niklas Loman PhD MD Consultant oncologist Skåne University Hospital Lund, Suecia

4 Prognosis in BRCA associated breast cancer Chemotherapy in early and recurrent BRCA-associated breast cancer Contra- and ipsilateral breast cancer risk, and management The risk of ovarian cancer, and the importance of ovarian cancer prevention BRCA as a clinical biomarker in breast cancer now and in the future

5 BRCA1: High Grade Triple negative Basal like BRCA2: High Grade ER-positive Luminal B Thanks Dr Dorthe Grabau

6 BRCA1: High Grade Triple negative Basal like BRCA2: High Grade ER-positive Luminal B Goodwin et al JCO 2012

7 Chemo sensitivity in BRCA- positive breast cancer Kriege et al 2009: 1st line chemo metastatic (CMF/antracycline) Wang et al 2014: Higher pcr rate in BRCA1- carriers compared with sporadics

8 Adjuvant chemotherapy in early onset (<41) BC: OS carriers vs non-carriers HR = 1,8 (1,0-3,3) OS adjuvant chemo HR 1,1 (0,5-2,5) OS no adjuvant chemo HR 3,0 (1,2-7,7) N= BRCA-tested cases Observe, non-randomized data! Nilsson et al. Breast Cancer Res Treat 2014

9 Platinum in BRCA-associated early breast cancer the polish experience: Type of chemo seems to matter: Regimen N= % pcr CMF 14 7 % AT 25 8 % FAC 28 21% AC 23 22% Cisplatinum % Byrski et al 2010

10 Platinum in BRCA1-associated early breast cancer the polish experience: The type of chemo seems to matter: Regimen N= % pcr CMF 14 7 % AT 25 8 % FAC 28 21% AC 23 22% Cisplatinum % Byrski et al x cis Surgery N= % pcr Byrski et al 2014

11 BRCA1 and BRCA2 - adverse prognostic phenotypes Multivariate: no major difference in survival probablility after BC sensitive to adjuvant chemo the type of chemo probably matters

12 Chemo in recurrent disease?

13 Randomized phase 2 Objective response primary end-point

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16 Surgical aspects

17 Graeser et al 25 years: 47 % risk of contralateral breast cancer Young age at first BC predicts increased risk B1: <40 63 % B1: > y BRCA1 > BRCA2

18 Effect on breast cancer specific survival of contralateral mastectomy? Metcalf et al 2014 Retrospective cohort N=390 BRCA carriers, stage 1-2BC 181 contralateral ME FU median 13y (0,1-20)

19 Survival post 10 years HR y10-20 =.30 ( ) HR y 0-10 =.65 ( ) Suggests beneficial effect on breast cancer survival in favour of contralateral ME in BRCAcarriers in the long run

20 High risk of new breast events after breast conserving treatment in BRCA mutation carriers CBC IBTR Comment Garcia-Etienne % vs 1 10y 27% vs 4 10y (HR=3,9 1,1-13,8) Case-control: N=54 BRCA1/2, 162 sporadic Haffty % vs 12y 49 % vs 21 12y Cohort study: N=17 BRCA1/2; N=105 non-brca Kirova % vs 13y 45% vs 24 % Case-Control: 29 BRCA, 271 sporadic Metcalf 2011 Pierce % vs 7 15 y 15 y (87 % had RT) No 10y: 34% 24 % vs y Cohort study: N=396 BRCA stage 1-2, BCT Case-Control study N= Pierce y 15y (?) Cohort study N=655 (N=302 BCT) Nilsson 32 15y Cohort study N=45

21 BC recurrence effect of type of surgery High risk of in breast recurrence after breast conservation Few local recurrences five years after a mastectomy No observed effect on DFS Ipsilateral recurrence Distant recurrence Breast Cancer res and Treat 2014

22 Ovarian cancer after breast cancer Domchek et al JAMA 2010

23 Benefit of SOE after BC Prospective cohort study 2482 BRCA mutation carriers, 4,4 years of FU: BRCA1 BRCA2 total SOE yes N=339 N=135 N=474 Peritonal ca 1,2% 0 1,0% SOE no N=345 N=241 N=586 Ovarian ca 7,8% 3,3% 6,0 % HR OC risk after SOE 0,15 (0,04-0,63 None 0,14 (0,04-0,59) HR OS after SOE 0,26 (0,13-0,52) 0,45 (0,17-1,17) 0,30 (0,17-0,52)

24 Benefit of SOE after BC BRCA1 BRCA2 total SOE yes N=339 N=135 N=474 Peritonal ca 1,2% 0 1,0% SOE no N=345 N=241 N=586 Ovarian ca 7,8% 3,3% 6,0 % HR OC risk after SOE 0,15 (0,04-0,63 None 0,14 (0,04-0,59) HR OS after SOE 0,26 (0,13-0,52) 0,45 (0,17-1,17) 0,30 (0,17-0,52)

25 Benefit of SOE after BC BRCA1 BRCA2 total SOE yes N=339 N=135 N=474 Peritonal ca 1,2% 0 1,0% SOE no N=345 N=241 N=586 Ovarian ca 7,8% 3,3% 6,0 % HR OC risk after SOE 0,15 (0,04-0,63 None 0,14 (0,04-0,59) HR OS after SOE 0,26 (0,13-0,52) 0,45 (0,17-1,17) 0,30 (0,17-0,52)

26 BRCA as a clinical biomarker in breast cancer

27 Risk assessment tool previously healthy Yes indeed since 20 years! Selects healthy individuals for targeted risk management Selects individuals not needing extra surveillance!

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29 Risk assessment tool after breast cancer Identifies breast cancer patients at managable increased risk of: Ovarian cancer Contralateral breast cancer Ipsilateral breast cancer

30 Not really! Prognostic marker? Associated with other adverse prognostic markers Adjuvant medical treatment may compensate

31 Treatment predictive marker Potentially (probably!) ongoing research will elucidate! Identify individuals with a potential benefit from certain types of chemotherapy (DNA-damaging, antracyclins) PARPinhibitors

32 In conclusion, early BRCAassociated breast cancer Be aware of BRCA! most BRCA-mutation carriers remain undetected! Test for BRCA! TNBC (BRCA1) Positive family history of breast and/or ovarian cancer Paternal inheritance? Prostate and pancreatic cancer Treat the cancer! Adjuvant chemotherapy in most cases Platinum? Not standard in adjuvant treatment

33 early BRCA-associated breast cancer Ovarian cancer prevention Potentially greater effect than adjuvant chemo! Awareness of increased contralateral breast cancer risk Risk reducing surgery? Awareness of increased risk of ipsilateral recurrence Consider mastectomy rather than breast conservation. Breast reconstruction!

34 Metastatic BRCA-associated breast cancer Consider platinum based chemotherapy early! Participate in clinical trials!

35 Thus, today: BRCA a standard biomarker in breast cancer! Cancer genetic counselling and BRCA testing needs to be part of initial assessment TEST FOR BRCA!

36 The future Breast preservation in BRCA-carriers?? Better risk prediction using genetic penetrance modifiers to identify low-risk carriers Effective directed breast cancer screening Effective targeted adjuvant treatments

37 Muchas gracias por su atención