Early Stage Disease. Hope S. Rugo, MD Professor of Medicine Director Breast Oncology and Clinical Trials Education UCSF Comprehensive Cancer Center

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1 SABCS 2014: Early Stage Disease Hope S. Rugo, MD Professor of Medicine Director Breast Oncology and Clinical Trials Education UCSF Comprehensive Cancer Center Topics for Discussion Chemotherapy plus 10 year update of E1199: what is the best taxane dose and schedule? NSABP B36: is more anthracycline better? Chemotherapy for older women? Bevacizumab in TNBC: outcome better than expected HER2+ disease Who benefits from trastuzumab? Hormone therapy SOFT: Optimal hormone therapy for premenopausal women 1

2 E1199: Compare Taxane Type and therapy in Stage IIA-IIIA Breast Cancer 4954 women enrolled, all subtypes (TN, ER+: 69%, HER2+: 20%) ACq3weeksx4followedby: Weekly paclitaxel x 12 Q3 week paclitaxel x 4 Weekly docetaxel x 12 (35 mg/m2) Q3 week docetaxel x 3 (100 mg/m2) 90% followed for at least 10 yrs: median FU 12.1 yrs Other reports BMI > 30 mg/m2 associated with worse outcome in ER+ disease Black race associated with worse outcome in ER+ disease No association between neuropathy and clinical outcome Primary comparisons (DFS and OS) P1/P3 vs D1/D3: no difference P1/D1 vs D3/P3: no difference Sparano SABCS 2014, Cancer 2012, JNCI 2012; Schneider JCO 2012 E1199: 10 Year Update Taxane by schedule interaction tests via stratified Cox model P=0.007 for OS P<0.001 for DFS OS: D1/P3 OS: D3/P (0.88, 1.18) 0.86 (0.73, 1.00) OS: P1/P (0.75, 1.02) DFS: D1/P3 096( (0.84, 110) 1.10) DFS: D3/P (0.68, 0.90) DFS: P1/P (0.73, 0.96) Hazard ratios and 95% CI from stratified Cox models HR for P1/P3 HR for D3/P3 HR for D1/P3 95% CI for P1/P3 95% CI for D1/P3 95% CI for D3/P3 2

3 E1199: Subsets In 1025 pts with TNBC: P1 vs P3 Improved OS from 66 to 75% (HR.69) Improved DFS from 59 to 69% (HR.69) This improvement was not seen with q3 wk docetaxel In 2785 pts with HR+/HER2 neg disease: D3 vs P3 Improved DFS from 69 to 75% (HR.76); no difference in OS Strong associations with inferior outcomes observed for: Obesity (BMI > 30 kg/m2) Black race independent of obesity, and confirmed in other reports How to improve on these results? NRG-BR003 for node positive/high risk node negative TNBC AC followed by weekly paclitaxel x 12 +/- carboplatin Pan et al. J Clin Oncol 2014; 32:5s (suppl; abstr 503); Lu et al. J Clin Oncol 2011; 29: 3358 NSABP B36: Is Longer Better? Node negative breast cancer: 2,722 patients (2004-8) AC x 4 vs. FEC 100 x 6 Initially 2 x 2 study with celecoxib: closed after 327 entered Amended to allow sequential trastuzumab if HER2+ in 2005 Median FU: 7 years, FU available in 99% 35% ER negative 50% T<2 cm, 44% grade 3 11% received trastuzumab Toxicity: increased with FEC100 (LVSD 0.1%) Efficacy DFS at 8 years: 82% in both arms, no difference in OS (92%) 1.5% mortality, 4.7% distant recurrence Jacobs et al (presented by Geyer), SABCS

4 ICE: Adjuvant Ibandronate +/- Capecitabine 1358 N+/N- high risk; age > 65 Ibandronate 50 mg PO daily or 6 mg IV 4wks x 2 years +/- Capecitabine 2000mg/m 2 14 day on, 7 d off x 6 cycles Hormone therapy as indicated, no trastuzumab Median age 71; 81% HR+; 18.5% HER2+; TN 14% 76% completed ibandronate; 83% completed cape Invasive disease free survival at 5 years 78.8 vs 75% (HR 1.04) No difference in any subgroup OS at 5 years: 90 vs 88% 25% had bone related events (not mets) Hormone therapy is a good thing in older women with HR+ early stage higher risk breast cancer Role of chemotherapy? CALGB 49907, Muss et al, NEJM 2009) von Minckwitz et al, SABCS 2014 BEATRICE: Median FU 56 mo women with TNBC, early stage Randomized to chemo with or witthout bevacizumab Outcome at 5 years OS: 88% DFS: ~78.5% No benefit from bevacizumab Chemotherapy is highly effective in early stage TNBC Bell et al, SABCS

5 HER2+ Disease: NSABP B-31 Subset B-31 (N=1578) 5% 6% 14% 28% 47% Basal-like HER2- enriched Luminal A Luminal B Normal-like HER2 negative (n=146) 3% 22% 23% 5% 47% ER negative (N=737) N=1578 ER positive (N=841) 2% 1% 6% 2% 8% 13% 25% 26% 71% 46% Pogue-Geile et al (presented by Paik), SABCS 2014; Pogue-Geile et al, JCO 2015 PAM50 RORP and RORS 5

6 N=672 8 PIK3CA hot spot mutations: Frequency in B31 = 24.7% Unlike neoadjuvant and metastatic data: no prognostic impact Association between Intrinsic Subtypes and HER2, ER, and 8-gene Predictive Signature 8-gene predictive model validation set (Pogue-Geile et al, JNCI 2013) In multivariate analysis: 8-gene ACT ACTH predictive model group 2 (n=449) was the only ACTH ACT HR 0.60( ) significant predictive P=0.011 marker P<.0001 of trastuzumab benefit group 1 (n=100) HR 1.58 ( ) P=0.29 Interaction p= (ESR1, CA12, GATA3, IGFR1, NAT1, ERBB2, GRB7, C17orf37) ACTH group 3 (n=442) HR 0.28( ) ACT Pogue-Geile et al, JNCI

7 Summary PAM50 intrinsic subtype or PIK3CA mutation did not identify subgroups without benefit from trastuzumab NSABP B47 is investigating the activity of trastuzumab in HER2 negative early stage BC Differential benefit in micrometastatic disease? Cancer stem cells from HER2 negative breast cancer cells are inhibited by trastuzumab Advanced or Neoadjuvant setting Adjuvant setting Trastuzumab started t at the time of tumor cell injection inhibit tumor growth of HER2 negative BC cells Ithimakin et al, Cancer Res 2013 This article was published on December 11,2014, at NEJM.org. 7

8 What are the Questions? For premenopausal women with hormone responsive early stage breast cancer, how much is enough? Should all/any women have their ovaries suppressed? SOFT If OS, tamoxifen or an AI? SOFT and TEXT combined analysis In whom can we avoid chemotherapy? No randomized trial Inferential data from SOFT/TEXT and ABCSG12 Is the bang worth the buck? Toxicity in SOFT How long should hormone therapy be given? What is the role of adjuvant bisphosphonates? Breast Cancer in Premenopausal Women Most frequent cancer diagnosis in women worldwide Most common cause of cancer death Age at diagnosis in the US (estimates for 2013) 21% in women < age 50 (~49,000) 4.7% in women < age 40 (~11,000) Hormone receptor positive still the most common subtype Incidence, particularly in younger women, has increased in the last decade 8

9 Outcome at 15 years with Tamoxifen ER+ disease, entry age < 45 years, 79% chemotherapy (n-2614) EBCTCG, Lancet 2011 Disease-Free Survival for Women Under 40 Years: E5188 INT 0101 (n=436/1500, all N+) Probability yr DFS Age % 02 CAF 48% < 35 10% 0.2 CAFZ 55% % CAFZT 64% >39 71% Disease-Free Survival (Years) Davidson et al. J Clin Oncol,

10 Meta-Analysis of LHRH Agonists as Adjuvant Therapy for Premenopausal Women with HR+ Breast Cancer 9,022 women with HR+ disease; 6.8 years med FU Tamoxifen +/- LHRH agonist No significant decrease in risk of recurrence (HR.85) or death after recurrence (HR 0.84) Chemotherapy +/- tamoxifen: addition of LHRH agonist provides modest benefit Reduction in risk of recurrence of 12.2% (HR.88) Reduction in risk of death after recurrence of 15.1% 1% (HR.85) As effective as chemotherapy regimens used in these trials (no taxanes, mostly non-anthracycline) Suboptimal use of tamoxifen Cuzick, et al; LHRH Metaanlysis Group. Lancet. 2007;369:1714 Meta-analysis of LHRH agonists as adjuvant treatment in premenopausal patients with ER + breast cancer: Recurrence risk by age 35 years HR years HR years HR years HR years HR 0.85 N=9022 Significant interaction for recurrence of age for addition of LHRH agonist to chemotherapy with or without tamoxifen (p=0.046) Lancet. 2007;369:

11 NSABP B30: Impact of Type of Chemotherapy and Age on Amenorrhea and Outcome <40 > 40 NSABP B30 substudy (Swain et al, NEJM 2010) 1885 women, N+, receiving chemotherapy In women with ER+ disease: Amenorrhea for > 6 months predicted improved OS (HR 0.52, P=0.002) and DFS (0.51, P<0.001) Ganz P et al. J Clin Oncol 2011; Swain et al. NEJM 2010 Patient/tumor characteristics 23% < 40 yrs of age 76% T1, 30% node +, 20% grade 3 95% of women are alive at 7.9 years median FU Worse survival with AI Inadequate OFS? Role of zoledronate? At 8 years, numerical advantage but loss of significance for DFS & OS Gnant et al, Ann Oncol

12 Pfeiler et al, JCO 2011 TEXT and SOFT Designs Enrolled 11/03-1/11 Premenopausal < 12 weeks after surgery Planned OFS No planned chemo OR planned chemo Premenopausal < 12 weeks after surgery No chemo OR Remain premenopausal < 8 mos after chemo R A N D O M I Z E R A N D O M I Z E TEXT: 2672 Tamoxifen+OFS x 5 yr Exemestane+OFS x 5 yr SOFT: 3047 Tamoxifen x 5 yrs (1018) Tamoxifen+OFS x 5 yr (1015) Exemestane+OFS x 5 yr (1014) Joint Analysis N=4690 Median FU 5.7 years SOFT Primary Analysis N=2033 Median FU years Pagani et al, ASCO NEJM 2014, Francis et al, SABCS NEJM

13 Definition of Endpoints, Statistics Primary DFS Invasive recurrence, invasive i contralateral t l cancer, second malignancy, death without prior cancer event Secondary BCFI Invasive recurrence or contralateral breast cancerr DRFI Distant recurrence free interval OS Stratification factors: chemo (+/-), node status (+/-) Protocol amendment 2011 (before efficacy data) Primary analysis T/OFS vs T Secondary analysis E/OFS vs T Patient Characteristics SOFT TEXT No Chemo Chemo No chemo Chemo 47% (949) 53% (1084) 40% 60% Median age LN+ 9% 57% 21% 66% T > 2 cm 14% 47% 19% 53% Grade 1 41% 14% 26% 12% Grade 3 7% 35% 12% 37% HER2+ve 4% 18% 5% 17% SOFT unique design Those who received chemotherapy had to recover ovarian function by 8 months (measured by serum estradiol) to be eligible Tamoxifen allowed during that time In women < 35 years, 94% received chemotherapy 13

14 Primary Analysis: Disease-free Survival 5.6 years median follow-up Primary analysis in overall population not significant (p=0.10) Multivariable Cox model HR=0.78 (95% CI ) p=0.03 Secondary Objectives E + OFS vs T alone: 4.3% absolute improvement (HR.68) E + OFS vs T alone: 4.5% absolute improvement (HR.64) T+OFS v T: 19% relative reduction in BC recurrence, p=0.09 E+OFS v T: 36% relative reduction in BC recurrence, 5y BCFI >90% 14

15 Premenopausal: No Chemotherapy Cohort selected for low risk clinicopathologic features 90% age 40yr, 91% node negative, 85% tumor 2cm, 41% grade 1 DFS: Summary: Overall Population No additional benefit adding OFS to T in the entire population E + OFS vs T alone: 4.3% absolute improvement (HR.68) Breast Cancer-Free Interval (BCFI): No significant improvement adding OFS to T E + OFS vs T alone: 4.5% absolute improvement (HR.64) Patients not receiving adjuvant chemotherapy (949): Physicians were able to select patients with excellent outcome regardless of endocrine therapy at 5.6 yrs 1% mortality (10/949) 1.4% DRFI (13/949) Older, node negative, T1 tumors, almost half grade 1 15

16 Premenopausal: After Prior Chemotherapy T+OFS v T: Absolute improvement in 5-yr BCFI of 4.5% E+OFS v T: Absolute improvement in 5-yr BCFI of 7.7% and 5-yr DRFI of 4.2% All women < 35 years of age 350 patients (11.5%) under age 35 94% received chemotherapy in this age group 16

17 Results: Biology and Risk Drive Benefit of Ovarian Suppression BCFI in premenopausal women who retain ovarian production of estrogen following adjuvant chemotherapy T + OFS > T E + OFS >> T This difference is even greater in women < 35 yrs of age Endpoint Premenopausal after chemo BCFI in < 35 yo (94% received chemo) Absolute improvement at 5 years HR (95% CI) T + OFS v. T E + OFS v. T BCFI 45% 4.5% 77% 7.7% 0.78 ( ) 0.65 ( ) DRFI 1.2% 0.87 (, ) 4.2% 0.72 ( ) 11.2% 15.7% DRFI: distant recurrence free interval BCFI: breast cancer free interval; Endpoint All patients combined TEXT + SOFT Joint Analysis BCFI DRFI Absolute improvement at 5 years E + OFS vs T + OFS 4% 1.8% No chemotherapy (TEXT only) Premenopausal after/with chemo BCFI 3% (HR 0.41) TEXT vs SOFT BCFI 5.5 vs 3.9% DRFI 2.6 vs 3.4% TEXT, no chemotherapy: 21% node positive, 16% < 40, 19% T > 2 cm DRFI: distant recurrence free interval BCFI: breast cancer free interval; Pagani et al, NEJM

18 Cost of Treatment: Toxicity 15% stopped OFS by 2 years, 22% by 3 years. Provider reported, clinically important Depression reported in ~ 50%, 4% severe, 5% increase with OFS Increase in menopausal symptoms, osteoporosis, insomnia most marked Patient reported (85% of trial population) No difference in global QOL with use of OFS in primary analysis despite differences in endocrine symptoms Global QOL indicators do not reflect important endocrine effects Endocrine differences are less pronounced after 2 years Compliance or adjustment to menopause? Endocrine toxicity overall less in women with prior chemotherapy Ribi et al, SABCS 2014 Selected Adverse Events T+OFS (N=1005) T (N=1006) CTCAE v3.0 Grade 1-4 Grade 3-4 Grade 1-4 Grade 3-4 Hot flushes/flashes 93% 13% 80% 8% Sweating 62% -- 48% -- Libido decrease 47% -- 42% -- Vaginal dryness 50% -- 42% -- Depression 52% 4% 47% 4% Insomnia 57% 5% 46% 3% Musculoskeletal 75% 5% 69% 6% symptoms Osteoporosis 20% (6%) 0.3% 12% (3%) 0.1% (% T< -2.5) Hypertension 23% 7% 17% 5% Glucose intolerance 3% 1% 2% 0.3% (diabetes)* Hyperglycemia* 5% 1% 2% 0.1% Any Gr 3-4 targeted AE -- 31% -- 24% *Added during trial conduct, may be under-reported 18

19 Treatment Effect: by Cohort Changes from baseline to month 6 for selected indicators Ribi et al, SABCS 2014 Treatment Effect: Global QoL E+OFS 19

20 Take Home Points and Additional Thoughts Successful international collaboration Accrual period 8 years Rigorous definition of menopausal status Clear and stringent definition of hormone receptor positive disease >10% by IHC Long follow-up planned; tissue analyses offer great potential Excellent and careful assessment of patient reported outcomes Its still early! Short follow-up for distant recurrence and overall survival Attention needs to be paid to management of toxicity Endocrine symptoms Depression Hypertension Bone health Sexual dysfunction Risk vs benefit requires individualization Role of genomic tests in decision making for intermediate risk patients? 2014: New Algorithm for Premenopausal Hormone Receptor Positive Disease? No chemotherapy Premenopausal Hormone receptor positive early stage breast cancer Chemotherapy Low risk Smaller tumors Node negative Grade 1 Older Intermediate risk Low grade but larger tumor Low grade but node positive High risk Larger tumors Node positive Grade 3 Younger T x at least 5 years Duration? Chemo + OS/T or E? OS + endocrine rx? OS + T or E > T (particularly in < 35 yo) OS + E > OS + T 20