Adjuvant Therapy of Breast Cancer Christy A Russell

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

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

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 in Chemotherapy?

What’s New with Chemotherapy? • ER (+), HER 2 (-) Breast Cancer – We

What’s New with Chemotherapy? • ER (+), HER 2 (-) 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 Mamma. Print has any predictive value at all over clinical features for chemotherapy benefit. – We await completion of the Rx. Ponder trial for ER(+), lymph node (+) patients.

TAILORx schema Trial Assigning Individualized Options for Treatment Recurrence Score® result ≤ 10 Hormone

TAILORx schema Trial Assigning Individualized Options for Treatment Recurrence Score® result ≤ 10 Hormone therapy registry Patients with node-negative, hormonepositive 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 *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

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=3300 (55%) N=2100 (35%) Clinicalpathological and 70 -gene both HIGH risk Discordant cases Clin-Path LOW 70 -gene HIGH Clin-Path HIGH 70 -gene LOW N=600 (10%) Clinicalpathological and 70 -gene both LOW risk Randomize Use Clin-Path risk to decide Chemo or not Adjuvant Chemotherapy (+ endocrine Tx if ER+) Use 70 -gene risk to decide Chemo or not Adjuvant Endocrine therapy only The goal of this trial is to show that Mamma. Print can spare 20 -30% of patients from adjuvant chemo Dr Martine Piccart-Gephart JBI, Brussels

Rx. Ponder Schema and Patient Flow Node-positive (1 -3 nodes) HR-positive and HER 2

Rx. Ponder Schema and Patient Flow Node-positive (1 -3 nodes) HR-positive and HER 2 -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 STEP 2 RANDOMIZATION STEP 1 REGISTRATION Tumor tissue submission for RS RECURRENCE SCORE RS > 25 (N= 3, 800) Discuss alternative trials for high risk patients RS < 25 N= 5, 600 Physician and patients discuss randomization knowing the RS Refuse N= 1, 600 Record chosen therapy and followed for vital status through cancer registry (N= 600) RS already Available Physician and patients discuss randomization knowing the RS Accept 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 N= 2, 000 No Chemotherapy; appropriate endocrine therapy

What’s New with Chemotherapy? • ER (-), HER 2 (-) Early Breast Cancer –

What’s New with Chemotherapy? • ER (-), HER 2 (-) Early Breast Cancer – What is the best sequence for anthracyclines and taxanes? – Weekly or dose-dense paclitaxel? – For whom can we avoid anthracyclines (NSABP B 49)?

CONSORT diagram for the original protocol of Southwest Oncology Group S 0221 trial. Budd

CONSORT diagram for the original protocol of Southwest Oncology Group S 0221 trial. 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

(A) Kaplan-Meier disease-free survival plot for all randomly assigned patients by randomization arm. TN pts Budd G T et al. JCO 2015; 33: 58 -64 © 2015 by American Society of Clinical Oncology ER+ pts

(A) Kaplan-Meier disease-free survival plot for all randomly assigned patients by randomization arm. Budd

(A) Kaplan-Meier disease-free survival plot for all randomly assigned patients by randomization arm. Budd G T et al. JCO 2015; 33: 58 -64

NSABP B 49 Schema Node Positive, or High-Risk Node Negative, HER 2 Negative Stratification

NSABP B 49 Schema Node Positive, or High-Risk Node Negative, HER 2 Negative Stratification Number of Positive Nodes Hormone receptor status Randomization Arm 1 Anthracycline-based Chemotherapy* Chemotherapy per Investigator* • TAC x 6 • AC WP • dd. AC dd. P Arm 2 TC x 6

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

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

Premenopausal HR+ Early Breast Cancer • Adjuvant tamoxifen for > 5 years is recommended.

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%

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,

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

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

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 No chemotherapy cohort selected for low risk

SOFT: Outcomes by Chemotherapy No Prior Chemotherapy No chemotherapy cohort selected for low risk features: 90% > age 40 yr, 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

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,

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) SOFT Premenopausal patients with HR+ BC ≤ 12 wks after surgery (if no chemo) or ≤ 8 mos after chemo (N = 3066) Tamoxifen 20 mg/day + OFS* (n = 1328) Joint Analysis Exemestane 25 mg/day + OFS* (n = 1332) Tamoxifen + OFS* (n = 2344) Tamoxifen 20 mg/day + OFS* (n = 1016) Exemestane + OFS* (n = 2346) Exemestane 25 mg/day + OFS* (n = 1014) Tamoxifen 20 mg/day Pagani O, et al. ASCO 2014. Abstract LBA 1. *OFS § TEXT: triptorelin 3. 75 mg IM every 28 days for 6 mos, then optional bilateral oophorectomy or irradiation § SOFT: choice of method

Percent Alive and Disease Free Exemestane With Ovarian Function Suppression Improved DFS Difference 3.

Percent Alive and Disease Free Exemestane With Ovarian Function Suppression Improved DFS Difference 3. 8% at 5 yrs 5 -yr DFS 91. 1% 100 80 Patients, n 87. 3% 60 Exemestane + OFS (n = 2346) Tamoxifen + OFS (n = 2344) 40 20 E + OFS T + OFS 0 0 1 Events HR 95% CI P Value 216 0. 72 0. 60 -0. 85. 0002 298 2 3 4 5 HR (95% CI) 5 -Yr DFS, % E+ OFS T+ 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 2. 0 4. 0 6 Yrs Since Randomization Median follow-up: 5. 7 yrs . 25 . 50. 72 1. 0 Favors E + OFS Favors T + OFS § 60% of first failures involved distant sites, including soft tissue, bone, and viscera Pagani O, et al. ASCO 2014. Abstract LBA 1. Reprinted with permission.

Joint Analysis of TEXT and SOFT Exemestane + OFS vs Tamoxifen + OFS Outcome

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 v 3. 0, % Exemestane + OFS

TEXT and SOFT: Selected Adverse Events CTCAE v 3. 0, % Exemestane + OFS (N = 2318) Tamoxifen + OFS (N = 2325) Grades 1 -4 Grades 3/4 Depression 50 3. 8 50 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 5. 2 0. 8 Hypertension 23 6. 5 22 7. 3 Cardiac ischemia/infarction 0. 7 0. 3 0. 1 Thrombosis/embolism 1. 0 0. 8 2. 2 1. 9 CNS ischemia 0. 7 0. 3 0. 1 CNS bleeding 0. 6 < 0. 1 0. 9 0. 1 Hot flushes/flashes 92 10 93 12 Sweating 55 NR 59 NR Vaginal dryness 52 NR 47 NR Libido decrease 45 NR 41 NR Dyspareunia 31 2. 3 26 1. 4 Urinary incontinence 13 0. 3 18 0. 3 Pagani O, et al. ASCO 2014. Abstract LBA 1. Reprinted with permission.

Final Analysis of ABCSG 12 HR vs Tam 1. 13 (0. 88 -1. 45)

Final Analysis of ABCSG 12 HR vs Tam 1. 13 (0. 88 -1. 45) p=0. 33 DFS HR vs Tam 1. 63 (1. 05 -2. 52 p=0. 03 OS Gnant, et al Ann Oncol 2014

Adjuvant Endocrine Therapy for Premenopausal Women • Several evidence-based choices now available: – Tamoxifen

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

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

Rugo H. Commentary at 2014 SABCS

Challenges in Optimal Endocrine Therapy • Predictive markers beyond ER, PR • Understanding pathways

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

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; 2 P <. 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. 931. 08) 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 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

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

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.