Focus on hormonal therapy in breast cancer. Magdolna Solti, MD March 21, 2015

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1 Focus on hormonal therapy in breast cancer Magdolna Solti, MD March 21, 2015

2 Outline Neoadjuvant therapy Adjuvant therapy Metastatic disease

3 Neo-adjuvant therapy Aims To improve surgical options To obtain freedom from disease To gain information on tumor response, biology To optimize systemic therapy

4 Questions in ER+ breast cancer Can we avoid preoperative chemotherapy in some ER+ breast cancers? What is the optimal duration of endocrine therapy? SIZE is not the issue in studies avoiding adjuvant chemotherapy

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10 Duration of therapy? Overall reponse Clinical CR Path CR 4 months 45% 13% 2.5% 8 months 87% 42% 5% 12 months 95% 57.5% 17.5% 3 letrozole cohorts (Allevi et al. BJC 2013) TEAM IIa trial Exemestane x 6 mos (Fontein EJC 2014)

11 Chemo vs Endocrine therapy Median age 67/68 58% ER+/PR+ Semiglazov Cancer 2007; 110:

12 Outcomes No statistically significant differences Numerically higher breast conservation on endocrine therapy (33% vs 24%, p=0.06) Toxicity as expected Endocrine (n=121) Clinical response 65% 64% pcr 3% 6% Progression 9% 9% Chemotherapy (N=118)

13 HER2+ and endocrine therapy?

14 Rimawi, SABCS 2014)

15 ALTERNATE Trial - Open

16 Neoadjuvant endocrine therapy - summary Not all women need chemotherapy Neoadjuvant endocrine therapy improves surgical outcomes ER+ cancers respond more slowly To chemotherapy and endocrine therapy pcr not the goal of therapy Choice of therapy? What you would use in the adjuvant setting Longer duration improves response rates (6 mos vs 4 mos)

17 Adjuvant therapy What are the treatment options in premenopausal ER+ women? Does ovarian function suppression improve outcome? What is the optimal length of therapy?

18 Pieces of the Puzzle for Premenopausal Hormone-Responsive Breast Cancer TAMOXIFEN Bisphosphonates

19 Premenopausal HR+ Early Breast Cancer Adjuvant tamoxifen for 5 years is the standard of care The value of ovarian function suppression or ablation (OFS) for women who receive tamoxifen (T) is uncertain Women who develop chemotherapy induced ovarian suppression (amenorrhea) have a reduced risk of relapse Likelihood of chemotherapy induced amenorrhea correlated with older age; less likely in women <35 years age

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21 SOFT and TEXT SOFT: Suppression of Ovarian Function Trial TEXT: Tamoxifen and Exemestane Trial The role of ovarian suppression in premenopausal hormone-receptor positive early breast cancer

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29 SOFT and TEXT- Conclusions The overall premenopausal population did not benefit from the addition of OFS some do very well with tamoxifen alone For women at sufficient risk of recurrence to warrant adjuvant chemotherapy and who retained premenopausal estradiol, addition of OFS to tamoxifen reduced recurrence. OFS enables treatment with an aromatase inhibitor which further reduced recurrence in the higher risk cohort. Benefit is most striking in women under age 35. Addition of OFS increases menopausal symptoms, depression, hypertension, diabetes and osteoporosis.

30 Extended Adjuvant Endocrine Therapy Beyond 5 Years N=11,646

31 ATLAS: 10 vs 5 yrs of Tamoxifen Recurrence Breast Cancer Mortality

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33 Premenopausal HR+ Algorithm Low Risk Small, node ve, grade 1, older Intermediate Risk Large, grade 1 Grade 1, node +ve High Risk Larger tumor, node+ve Grade 3, Younger Tamoxifen x5-10 y Chemo + OS/T or E or OS + endocrine Chemo + OS +E > OS + T

34 Metastatic disease

35 Metastatic HR+ Breast cancer What causes resistance to endocrine therapies? What are the new treatment combinations to overcome endocrine resistance?

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39 Clonal expansion and genome evolution through cancer progression TTR:~ 6 yrs Small percentage of primary tumor seeds metastasis; `bottleneck event Long TTR is likely needed to observe bottleneck in breast cancer Metastases evolve extensively and gain many unique mutations Krøigård, Oncotarget 2015

40 Acquired resistance: biological basis

41 Targets in clinical trials for ER+ mbc Zardavas et al. Nat Rev Clin Onc 2013

42 BOLERO-2: everolimus + exemestane improves PFS but not OS OS

43 PALOMA-1: palbociclib + letrozole in first line ER+ advanced breast cancer Finn, Lancet Oncol 2015

44 Conclusions Biopsy and mutational analysis of metastatic disease is becoming increasingly important for optimal patient management Clinical trials should be embraced to test genome-driven combination studies

45 Be Informed. Be Educated. Be BRAVE.