Adjuvant Therapy of Breast Cancer Christy A Russell, MD Keck School of Medicine University of Southern California

Hazard Rate of Relapse According to Tumor Subtype and Year of Diagnosis British Columbia Population-Based Data 1986-1992 2004-2008 Cossetti, et al. JCO 2014

What’s New in Chemotherapy?

What’s New with Chemotherapy? ER (+), HER2 (-) Breast Cancer We await the publication of TAILORx to further refine the predictive value of Oncotype Dx (especially in the intermediate RS tumors). We await the publication of MINDACT trial to elicit whether MammaPrint has any predictive value at all over clinical features for chemotherapy benefit. We await completion of the RxPonder trial for ER(+), lymph node (+) patients.

TAILORx schema Trial Assigning Individualized Options for Treatment Recurrence Score® result ≤ 10 Hormone therapy registry Patients with node-negative, hormone-positive breast cancer Oncotype DX® assay Recurrence Score result 11-25* Randomize to either hormone therapy or chemotherapy + hormone therapy Register specimen banking Recurrence Score result > 25 Chemotherapy + hormone therapy Main point: The study schema of the TAILORx trial is shown here. The eligible patients for this trial are node-negative, ER+ and are candidates for chemotherapy (ie, patients who do not have comorbid conditions that would preclude them from receiving chemotherapy and who are willing to take it if recommended). The fact that the Breast Cancer Intergroup is stratifying patients for the TAILORx trial by the Oncotype DX® assay demonstrates that this assay is widely accepted and validated in the study population. Treatment will be based on the results of the assay. Patients will be stratified as follows: Patients with a Recurrence Score® result below 11 will receive hormonal therapy alone. Patients with a Recurrence Score between 11 and 25 will be randomized to either hormonal therapy alone or hormonal therapy + chemotherapy. This is the primary study group. This corresponds approximately to a risk of recurrence at 10 years of 10%-20% (at upper bound of 95% CI). Patients with a Recurrence Score greater than 25 will receive chemotherapy + hormonal therapy. Since this trial has a dealer’s choice–type design, individual investigators can select the type of hormonal therapy and chemotherapy from a list included in the protocol. The groups in this trial do not correspond to the low-, intermediate-, and high-risk cutoffs found on the Oncotype DX report. The treatment groups for the TAILORx trial were selected for different purposes from those involved with the selection of cutoffs for the validation trial and the Oncotype DX report.  The treatment groups for the TAILORx study were selected to correspond with specific levels of risk of recurrence and likelihood of chemotherapy benefit.  The TAILORx investigators felt it would not be ethical to withhold chemotherapy from women who have a 20% risk of recurrence This study has a non-inferiority design. The hypothesis is that patients in this middle-range Recurrence Score risk group will do no worse with hormonal therapy alone than they would with hormonal therapy plus from chemotherapy. Note: The study does not assess the validity of the Oncotype DX assay. This trial design is predicated on the assessment that the assay is fully validated. For a patient with a Recurrence Score < 11, chemo will not be given. For a patient with a Recurrence Score > 25, chemo will be given. The risk generated from the Recurrence Score result is felt to be validated and is actionable, based on the references below. Paik S, Shak S, Tang G, et al. N Engl J Med. 2004;351(27):2817-2826. Paik S, Tang G, Shak S, et al. J Clin Oncol. 2006 Aug 10;24(23) [Epub ahead of print May 23, 2006]. Habel L, Shak S, Jacobs M, et al. Breast Cancer Res. 2006;May 31;8(3):R25 [Epub ahead of print]. Simon R. J Clin Oncol. 2005;23(29):7332-7341. *Primary study group: Recurrence Score result 11-25 correlates with a 10-20% risk of distance recurrence at 10 years (upper 95% CI)

EORTC-BIG MINDACT TRIAL DESIGN 6,000 Node negative and 1-3 + lymph node breast cancer women Evaluate Clinical-Pathological risk and 70-gene signature risk N=2100 (35%) N=600 (10%) N=3300 (55%) Discordant cases Clinical-pathological and 70-gene both LOW risk Clinical-pathological and 70-gene both HIGH risk Clin-Path LOW 70-gene HIGH Clin-Path HIGH 70-gene LOW Randomize Use Clin-Path risk to decide Chemo or not Use 70-gene risk to decide Chemo or not Adjuvant Chemotherapy (+ endocrine Tx if ER+) Adjuvant Endocrine therapy only The goal of this trial is to show that MammaPrint can spare 20-30% of patients from adjuvant chemo Dr Martine Piccart-Gephart JBI, Brussels

RxPonder Schema and Patient Flow Node-positive (1-3 nodes) HR-positive and HER2-negative breast cancer (N= 8,800) Patients consent to study-sponsored RS testing, discussion of potential trials, tumor tissue submission and linkage to cancer registry data (N= 600) RS already Available Physician and patients discuss randomization knowing the RS STEP 1 REGISTRATION Tumor tissue submission for RS STEP 2 RANDOMIZATION RECURRENCE SCORE STEP 2 REGISTRATION/ RANDOMIZATION N= 4,000 Randomization stratified by 1. RS 0-13 vs. 14-25 2. Menopausal status 3. Axillary node dissection vs. Sentinel node biopsy N= 2,000 Chemotherapy; appropriate endocrine therapy RS > 25 RS < 25 (N= 3,800) Discuss alternative trials for high risk patients N= 5,600 Physician and patients discuss randomization knowing the RS Accept N= 2,000 No Chemotherapy; appropriate endocrine therapy Refuse N= 1,600 Record chosen therapy and followed for vital status through cancer registry

What’s New with Chemotherapy? ER (-), HER2 (-) Early Breast Cancer What is the best sequence for anthracyclines and taxanes? Weekly or dose-dense paclitaxel? For whom can we avoid anthracyclines (NSABP B49)?

CONSORT diagram for the original protocol of Southwest Oncology Group S0221 trial. CONSORT diagram for the original protocol of Southwest Oncology Group S0221 trial. AC, doxorubicin-cyclophosphamide; Q2 week, once every 2 weeks. Budd G T et al. JCO 2015;33:58-64 ©2015 by American Society of Clinical Oncology

(A) Kaplan-Meier disease-free survival plot for all randomly assigned patients by randomization arm. TN pts ER+ pts (A) Kaplan-Meier disease-free survival plot for all randomly assigned patients by randomization arm. Number at risk at the beginning of each 12-month period is shown in the table. Three patients with no follow-up were excluded. (B) Kaplan-Meier overall survival plot of all randomly assigned patients by randomization arm. Three patients with no follow-up were excluded. (C) Kaplan-Meier disease-free survival plot by randomization arm for patients with triple-negative tumors (estrogen receptor negative, progesterone receptor negative, and human epidermal growth factor receptor 2 [HER2] negative). (D) Kaplan-Meier disease-free survival plot by randomization arm for patients with hormone receptor–positive (estrogen receptor–positive and progesterone receptor–positive) and HER2–negative tumors. 2wAC, doxorubicin-cyclophosphamide once every 2 weeks; AC + G, doxorubicin-cyclophosphamide with filgrastim; q 2 weeks, once every 2 weeks. Budd G T et al. JCO 2015;33:58-64 ©2015 by American Society of Clinical Oncology

(A) Kaplan-Meier disease-free survival plot for all randomly assigned patients by randomization arm. (A) Kaplan-Meier disease-free survival plot for all randomly assigned patients by randomization arm. Number at risk at the beginning of each 12-month period is shown in the table. Three patients with no follow-up were excluded. (B) Kaplan-Meier overall survival plot of all randomly assigned patients by randomization arm. Three patients with no follow-up were excluded. (C) Kaplan-Meier disease-free survival plot by randomization arm for patients with triple-negative tumors (estrogen receptor negative, progesterone receptor negative, and human epidermal growth factor receptor 2 [HER2] negative). (D) Kaplan-Meier disease-free survival plot by randomization arm for patients with hormone receptor–positive (estrogen receptor–positive and progesterone receptor–positive) and HER2–negative tumors. 2wAC, doxorubicin-cyclophosphamide once every 2 weeks; AC + G, doxorubicin-cyclophosphamide with filgrastim; q 2 weeks, once every 2 weeks. Budd G T et al. JCO 2015;33:58-64

NSABP B49 Schema Node Positive, or High-Risk Node Negative, HER2 Negative Stratification Number of Positive Nodes Hormone receptor status Randomization Arm 1 Anthracycline-based Chemotherapy* Arm 2 TC x 6 Chemotherapy per Investigator* TAC x 6 AC  WP ddAC WP ddAC  ddP

What’s New for ER (+) Early Breast Cancer in Premenopausal Women?

Premenopausal HR+ Early Breast Cancer Adjuvant tamoxifen for > 5 years is recommended. Genomic profiles are being developed to guide us on which women will benefit from > 5 years of tamoxifen. The value of ovarian function suppression or ablation for women who receive tamoxifen is uncertain. Women who develop chemotherapy-induced amenorrhea have a reduced risk of relapse.

Outcome at 15 years with Tamoxifen ER+ disease, entry age < 45 years, 79% chemotherapy (n=2614) EBCTCG, Lancet 2011

Options for Premenopausal Women Standard of care has been tamoxifen for 5 years, but > 5 years looks better in some. What is the role of ovarian ablation in women receiving tamoxifen? SOFT What is the role of ovarian ablation with an AI? SOFT, TEXT, ABCSG-12

SOFT Primary Analysis: DFS 5.6 years median follow-up > 95% Overall survival Primary analysis in overall population not significant (p=0.10) Multivariable Cox model HR=0.78 (95% CI 0.62-0.98) p=0.03 Francis, et al. NEJM 2014

SOFT Secondary Objectives T + OFS vs T: 19% relative reduction in breast cancer recurrence p= 0.09 E + OFS vs T: 36% relative reduction in breast cancer recurrence CI (0.49-0.83) Francis, et al. NEJM 2014

SOFT: Outcomes by Chemotherapy No Prior Chemotherapy Prior Chemotherapy No chemotherapy cohort selected for low risk features: 90% > age 40yr, 91% node negative, 85% tumor <2 cm, 41% grade 1 Francis, et al. NEJM 2014

Cost of Treatment: Toxicity 15% stopped OFS by 2 years, 22% by 3 years. Provider-reported, clinical important Depression reported in ≅ 50%, 4% severe, 5% increase with OFS Increase in menopausal symptoms, osteoporosis, insomnia most marked Patient reported No difference in global QOL with use of OFS in primary analysis 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

TEXT and SOFT Trials: Comparison of Tamoxifen or Exemestane With OFS Stratified by trial, use of chemotherapy, nodal status 5 yrs TEXT Premenopausal Patients with HR+ BC ≤ 12 wks after surgery (N = 2672) Joint Analysis Tamoxifen 20 mg/day + OFS* (n = 1328) Exemestane 25 mg/day + OFS* (n = 1332) Tamoxifen + OFS* (n = 2344) SOFT Tamoxifen 20 mg/day + OFS* (n = 1016) Exemestane + OFS* (n = 2346) Premenopausal patients with HR+ BC ≤ 12 wks after surgery (if no chemo) or ≤ 8 mos after chemo (N = 3066) BC, breast cancer; HR+, hormone receptor positive; IM, intramuscularly; OFS, ovarian function suppression. Joyce O’Shaughnessy, MD: The TEXT and SOFT trials were randomized open-label multicenter phase III trials undertaken to identify the optimal endocrine therapy in premenopausal patients with hormone receptor–positive breast cancer. Patients received either tamoxifen or exemestane, each combined with ovarian function suppression (OFS) therapy, or tamoxifen alone. It is important to point out here that OFS with triptorelin was started concurrently with chemotherapy in the TEXT trial, if chemotherapy was indicated in the adjuvant setting. So, the TEXT trial did not focus on a group of patients who still had documented ovarian function after completion of chemotherapy. Whereas in the SOFT trial, patients were enrolled within 8 months of finishing adjuvant chemotherapy, if indicated, and did have to have documented ovarian function (estradiol in the premenopausal range) prior to enrollment in the SOFT trial.   These data were the biggest news at ASCO and something that we need to grapple with in terms of how to integrate this in our practice, which underscores the global importance of this SOFT and TEXT data. Exemestane 25 mg/day + OFS* (n = 1014) *OFS TEXT: triptorelin 3.75 mg IM every 28 days for 6 mos, then optional bilateral oophorectomy or irradiation SOFT: choice of method Tamoxifen 20 mg/day Pagani O, et al. ASCO 2014. Abstract LBA1.

Exemestane With Ovarian Function Suppression Improved DFS 60% of first failures involved distant sites, including soft tissue, bone, and viscera Difference 3.8% at 5 yrs Patients, n HR (95% CI) 5-Yr DFS, % E + OFS T + OFS E + OFS All Patients 2346 2344 91.1 87.3 Cohort No chemotherapy, TEXT No chemotherapy, SOFT Chemotherapy, TEXT Prior chemotherapy, SOFT 526 470 806 544 527 473 801 543 96.1 95.8 89.8 84.3 93.0 93.1 84.6 80.6 Lymph Node Status Negative Positive 1362 984 1350 994 95.1 85.6 91.6 81.4 5-yr DFS 100 91.1% 80 87.3% 60 Exemestane + OFS (n = 2346) Tamoxifen + OFS (n = 2344) Percent Alive and Disease Free 40 Events 216 298 HR 0.72 95% CI 0.60-0.85 P Value .0002 20 E + OFS T + OFS DFS, disease-free survival; E, exemestane; OFS, ovarian function suppression, T, tamoxifen. Joyce O’Shaughnessy, MD: The authors presented data from the groups that received either tamoxifen plus OFS or exemestane plus OFS; data from the SOFT trial for the group that received tamoxifen alone has not yet been presented. As shown in the Kaplan-Meier curve, there was a 3.8% absolute improvement in 5-year DFS for patients in the exemestane plus OFS arm compared with tamoxifen plus OFS, and a 2% improvement in distant DFS. Interestingly, the proportion of patients who were disease free was very similar between the 2 arms for the first 2 years of the study before diverging. We know that breast cancers that recur within the first 5 years are biologically more proliferative and more aggressive, and we have seen that aromatase inhibitors offer benefit vs tamoxifen in postmenopausal women at risk for early recurrence. So, aromatase inhibitors are probably most essential for those patients with aggressive disease. Whereas at least in the postmenopausal setting, if patients have more indolent grade I/II breast cancer, initiating treatment with tamoxifen and then switching over to an aromatase inhibitor is probably sufficient, and I think the same general concept is true here as well. I think these data emphasize that aromatase inhibitors are more beneficial than tamoxifen for aggressive disease regardless of menopausal status.   Regarding the chemotherapy and no chemotherapy comparison for SOFT and TEXT in the forest plot, the disease-free status results are a bit better in TEXT than in SOFT. Although the reason for this difference in unclear, the question here is: If we are going to use luteinizing hormone-releasing hormone (LHRH) agonist, do we use the TEXT protocol and start from Day 1? Although the difference of the 5.2% absolute improvement with the TEXT vs 3.7% improvement with SOFT should be interpreted cautiously, the TEXT trial data give me permission to do so. When we give chemotherapy, we are postponing for 4-6 months the most important therapy, which is endocrine therapy. This is particularly true in patients under 35 with very strong ovarian function. So I am actually very happy to see the TEXT data, including their use of a LHRH agonist in the young than 40 years of age and higher-risk population from Day 1. 1 2 3 4 5 6 .25 .50 .72 1.0 2.0 4.0 Yrs Since Randomization Median follow-up: 5.7 yrs Favors E + OFS Favors T + OFS Pagani O, et al. ASCO 2014. Abstract LBA1. Reprinted with permission.

Joint Analysis of TEXT and SOFT Exemestane + OFS vs Tamoxifen + OFS Outcome HR (95% CI) p value DFS 0.72 (0.60-0.85 0.0002 BCFI 0.66 (0.55-0.80) <0.0001 DDFI 0.78 (0.62-0.97) 0.02 OS 1.14 (0.86-1.51) 0.37 Median Follow-up of 5.7 years Pagani et al. NEJM 2014

TEXT and SOFT: Selected Adverse Events CTCAE v3.0, % Exemestane + OFS (N = 2318) Tamoxifen + OFS (N = 2325) Grades 1-4 Grades 3/4 Depression 50 3.8 4.4 Musculoskeletal 89 11 76 5.2 Osteoporosis (%Tscore < -2.5) 39 (13) 0.4 25 (6) 0.3 Fracture 6.8 1.3 0.8 Hypertension 23 6.5 22 7.3 Cardiac ischemia/infarction 0.7 0.1 Thrombosis/embolism 1.0 2.2 1.9 CNS ischemia CNS bleeding 0.6 < 0.1 0.9 Hot flushes/flashes 92 10 93 12 Sweating 55 NR 59 Vaginal dryness 52 47 Libido decrease 45 41 Dyspareunia 31 2.3 26 1.4 Urinary incontinence 13 18 CNS, central nervous system; NR, not reported; OFS, ovarian function suppression. Joyce O’Shaughnessy, MD: This slide shows the toxicities related to these treatment approaches. It can be difficult for a young woman to undergo treatment with an LHRH agonist and an aromatase inhibitor or tamoxifen regarding depression, musculoskeletal, osteoporosis, and hot flashes. There are many adverse effects here, and this can be a very challenging issue for us in practice. Pagani O, et al. ASCO 2014. Abstract LBA1. Reprinted with permission.

Final Analysis of ABCSG 12 HR vs Tam 1.13 (0.88-1.45) p=0.33 HR vs Tam 1.63 (1.05-2.52 p=0.03 DFS OS Gnant, et al Ann Oncol 2014

Adjuvant Endocrine Therapy for Premenopausal Women Several evidence-based choices now available: Tamoxifen x 5-10 yr Tamoxifen x 5 yr to AI x 5 yr (MA-17) OFS + Tamoxifen OFS + AI Davidson N, Commentary SABCS 2014

Adjuvant Endocrine Therapy for Premenopausal Women Tamoxifen alone x 5-10 years sufficient for low risk Consider use of OFS + Tam or OFS + AI for higher risk women Chemotherapy recipients Multiple positive nodes Age < 35 Optimal duration of OFS-based therapy uncertain Long-term follow-up for both benefit and toxicity Davidson N, Commentary SABCS 2014

Rugo H. Commentary at 2014 SABCS

Challenges in Optimal Endocrine Therapy Predictive markers beyond ER, PR Understanding pathways of resistance and when they come into play Optimizing the host environment – BMI? Monitoring the long-term benefit and toxicity Compliance and adherence of the patient (and their health care provider) Davidson N, SABCS 2014 Commentary

Obesity in Breast Cancer Early Breast Cancer Trialists’ Collaborative Group collected data on 80,000 patients with early breast cancer to analyze independent effects of BMI on patient outcome Obesity independently associated with BC-related mortality in premenopausal pts with ER+ BC In premenopausal obese (BMI ≥ 30) vs normal-weight women with ER+ disease (N = 20,000): 10-yr BC-relate mortality: 21.5% vs 16.6% (RR = 1.34; 95% CI: 1.22-1.47; 2P < .00001) Little effect in premenopausal women with ER-negative disease or in postmenopausal women Postmenopausal ER+ (N = 40,000): RR = 1.06 (95% CI: 0.99-1.14) Pre- or postmenopausal ER-negative (N = 20,000): RR: 1.00 (95% CI: 0.93-1.08) BC, breast cancer; BMI, body mass index; ER+, estrogen receptor positive; RR, relative risk; SE, standard error. Joyce O’Shaughnessy, MD: The Early Breast Cancer Trialists’ Collaborative Group assessed the impact of body mass index on outcomes in 80,000 patients with early breast cancer. They found that obesity had a small prognostic impact on mortality risk in premenopausal, ER‑positive patients. I think this finding is important but something that we are not entirely sure of yet. We are still concerned about the ER‑negative patients who are obese. I would like to see additional datasets before concluding that obesity is only a risk factor in premenopausal ER‑positive patients. Pan H, et al. ASCO 2014. Abstract 503.

BMI: Impact on Efficacy of Endocrine Therapy in ABCSG-12 Pfeiler, et al. JCO 2011

BMI: Impact on Efficacy of Endocrine Therapy in ABCSG-12 Pfeiler, et al. JCO 2011

BMI: Impact on Efficacy of Endocrine Therapy in ABCSG-12 Conclusions These data are hypothesis generating secondary to the retrospective analysis. However, it does suggest that BMI influences the efficacy of OFS+ Anastrozole in premenopausal women when compared to tamoxifen +OFS. Because over 1/3 of premenopausal women who develop breast cancer are overweight or obese, consideration should be given regarding selection of endocrine therapy. Pfeiler, et al. JCO 2011

Conclusions Very little practice-changing data in the use of adjuvant chemotherapy. SOFT may present a new paradigm for young high-risk women with ER (+) early breast cancer. The role of BMI may need to be considered when selecting endocrine therapy for our patients.