Angelo Di Leo “Sandro Pitigliani” Medical Oncology Department Hospital of Prato Istituto Toscano Tumori, Prato, Italy Adjuvant hormone therapy in pre-menopausal women in 2016

ApplicabilityCompany (1) Advisory roleYes AstraZeneca, Bayer, Lilly, Novartis, Pfizer, Roche (2) Stock ownership/profit None (3) Patent royalties/licensing fees None (4) Lecture feesYes AstraZeneca, Eisai, Genomic Health, Novartis, Pfizer, Roche (5) Manuscript feesNone (6) Scholarship fundNone (7) Other remunerationNone Conflict of Interest Disclosure

Focus on endocrine therapy Three main options: - Tamoxifen - ovarian suppression + tamoxifen - ovarian suppression + aromatase inhibitor

SOFT trial 3047 pts randomized in ITT, Dec 2003-Jan 2011 Two patients cohorts No chemotherapy (47%) Premenopausal, within 12 w of surgery (median time since surgery = 1.8 m) Prior chemotherapy (53%) Premenopausal * after completing chemotherapy; Randomization within 8 m of completion (median time since surgery = 8.0 m) * According to locally determinated E 2 level in premenopausal range Tamoxifen x 5y (n=1018) Tamoxifen + OFS x 5y(n=1015) Exemestane + OFS x 5y (n=1014) Median follow-up 5.6 years Primary analysis (n=2033) RANDOMIZATION Francis PA et al, NEJM 2014 Primary end-point: disease free survival Median age: 43 yr; <35 yr: 11.5% N+ disease: 35% Primary analysis° ° The original statistical analysis plan for SOFT was to assess disease-free survival between the treatment groups with three pairwise comparisons. Due to the accrual of a more favorable pt population than the expected a protocol amendment to the analysis plan was adopted in 2011,designating the test of the superiority of tamoxifen plus ovarian suppression over tamoxifen alone as the primary analysis for SOFT

SOFT trial: primary analysis (n=2033) Francis PA et al, NEJM 2014 Median follow-up 5.6 years 5-yr DFS rate : 86.6% in the experimental and 84.7% in the standard arm (HR: 0.83; CI, ; P=0.10) Multivariable allowance for prognostic factors suggested a greater treatment effect with tam + OFS than with tam alone (HR, 0.78; CI, ; P=0.03)

Ais plus OFS (TEXT and SOFT) Tamoxifen vs. Exemestane n=4,690 RANDOMIZERANDOMIZE Tam Tam+OFS Exe+OFS RANDOMIZERANDOMIZE Tam+OFS Exe+OFS

Ais plus OFS (TEXT and SOFT) Exemestane+OFS improved DFS 5.7 years median follow-up Difference 3.8% at 5 years NEJM 2014; 371:

SOFT Selected Adverse Events NEJM 2015; 372:

TEXT Selected adverse events NEJM 2014; 371:

Role for Risk in Predicting Benefit of Endocrine Therapy Explore risk as a factor for treatment selection in premenopausal populations in TEXT and SOFT Focus on treatment selection for women with HER2-negative disease Composite risk score for breast cancer-free interval (BCFI) calculated using Cox model including: –age, nodal status, tumor size and grade, ER, PgR, Ki-67

STEPP of 5-year BCFI according to Composite Risk Score: Overall HER2-negative Median Composite Risk Score in Subpopulations yr N0 T≤2cm Grade 1 Ki67<14% ER ≥50% PgR ≥50% <35 yr N 4+ T>2cm Grade 3 Ki67 >26% ER <50% PgR <20% yr N 1-3 T≤2cm Grade 2 Ki % ER ≥50% PgR ≥50% yr N0 T>2cm Grade 3 Ki67 >26% ER ≥50% PgR ≥50% Courtesy of M. Regan

STEPP of 5-year BCFI according to Composite Risk Score: TEXT +/- Chemo Median Composite Risk Score in Subpopulations Exemestane + OFS Tamoxifen + OFS Courtesy of M. Regan

STEPP of 5-year BCFI according to Composite Risk Score: SOFT No Chemo Median Composite Risk Score in Subpopulations Exemestane + OFS Tamoxifen + OFS Tamoxifen Courtesy of M. Regan

STEPP of 5-year BCFI according to Composite Risk Score: SOFT Prior Chemo Median Composite Risk Score in Subpopulations Exemestane + OFS Tamoxifen + OFS Tamoxifen Courtesy of M. Regan

Tailoring endocrine therapy: Summary When comparing different endocrine therapies, proportional benefits seem to be independent of tumor stage or bio-markers However, increased risk of relapse increased absolute benefit Low riskHigh risk Tamoxifen Aromatase inhibitor + ovarian suppression

Pending issue: we need survival data from TEXT and SOFT ABCSG-12 Median f-up 94 mos. Survival curves TEXT Median f-up 68 mos. Survival curves Possible explanations - 86 vs. 194 deaths in ABCSG-12 vs. TEXT - 3 vs. 5 years of aromatase inhibitors in ABCSG-12 vs. TEXT - longer follow-up required for TEXT

Twelve-month estrogen levels in pre-menopausal women treated with Triptorelin plus Exemestane in the SOFT trial Bellet M et al. J Clin Oncol 34: , 2016

Correlation between patient characteristics and sub-optimal E2 levels suppression at ≥ 1 time point Bellet M et al. J Clin Oncol 34: , 2016

Additional questions age < 35 optimal duration of LH-RH analogue treatment

SOFT trial: outcomes for pts < 35 yr Francis PA et al, NEJM pts (11.5%) under age 35, 233 of whom were included in the primary analysis(Tam vs Tam+OFS) The rate of freedom from BC at 5 yr was 67.7% for pts assigned to Tam alone, 78.9% for those assigned to Tam+OFS and 83.4% for those assigned to E + OFS 94% of the pts had received CT

Optimal duration of LH-RH analogue treatment No evidence from randomized trials 2 5 yrs. treatment duration Factors Ageclose to 50<40 Tolerabilitypoorgood Risklowhigh

Acknowledgments