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Clinical Updates Hormonally Sensitive, Early-Stage Breast Cancer Current Considerations in the Management of Patients with Hormonally Sensitive Early-stage Breast Cancer Harold J. Burstein, MD, PhD Dana-Farber Cancer Institute Harvard Medical School Boston, MA Overview • Case 1: Optimizing Therapy in Postmenopausal Women – ER+, PR+, HER2 negative stage I breast cancer • Case 2: Optimizing Therapy in Premenopausal Women – Which patients with ER+ tumors should receive adjuvant chemotherapy? Case 1 • Postmenopausal Women – T = 0.8 cm – ER+ – PR+ – HER2 negative – Stage I breast cancer • What issues should be considered to optimize endocrine therapy for postmenopausal women? Key Issues in Adjuvant Endocrine Therapy for Postmenopausal Women • When to start an AI • When to stop an AI • Whether and how to use tamoxifen – Tumor features (ER, PR, HER2) – Clinical factors (patient preference, comorbidities) – Pharmacogenomic factors – Concurrent medication factors • Minimizing side effects, esp. bones • Late sequelae – good or bad – of AI therapy Importance of Endocrine Therapy • 2/3 of breast cancers are ER/PR+ • 3/4 of post-menopausal women have ER/PR+ tumors • Overall little toxicity from endocrine treatment • Significant benefit from optimizing use of endocrine agents in the post-menopausal population Adjuvant Endocrine Agents: Tamoxifen • Useful regardless of menopausal status • In postmenopausal women: – Reduces recurrence by 37 – 54% – Reduces death by 11 – 33% • Long-term side effects characterized • Carryover effect documented • Utility in sequence with AIs in post-menopausal women Early Breast Cancer Trialists, Lancet 2005. Adjuvant Endocrine Agents: Aromatase Inhibitors • Inhibit peripheral conversion of androgens to estrogens by the aromatase enzyme • 3 agents: anastrazole, letrozole, exemestane • Utility of adjuvant AIs established through 3 trial designs – Upfront comparison with tamoxifen • ATAC, BIG 1-98 – Sequential therapy after 2-3 years tamoxifen • IES, ARNO/ABCSG, ITA – Extended therapy after 5 years tamoxifen • MA.17 Adjuvant Trials AIs in Postmenopausal Women Tamoxifen x 5 years AI x 5 years Upfront vs Tamoxifen Tamoxifen x 5 years Tamoxifen AI Sequential vs Tamoxifen Placebo x 5 years Tamoxifen x 5 years AI x 5 years Extended Rx, AI vs Placebo 5 years of AI is Established • ATAC: 100 month follow-up • Lower recurrence rate after 5 years, suggests carryover effect • No new toxicity signals • No OS benefits Forbes et al, Lancet 2008 ATAC: 100 Month Follow-up Forbes et al, Lancet 2008 Big 1-98: 5-year Analysis DFS OS Coates, A. S. et al. J Clin Oncol; 25:486-492 2007 Coates et al, J Clin Oncol 2007;25:486-92 IES Update 2007 Coombes, et al. Lancet 2007;369:559 ARNO 95 / ABCSG 8 / ITA Pooled Outcomes Jonat, et al. Lancet Oncology 2006;7:991 MA.17 DFS OS Goss, P. E. et al. J. Natl. Cancer Inst. 2005 97:1262-1271; doi:10.1093/jnci/dji250 ASCO Guidelines “The Panel believes that optimal adjuvant hormonal therapy for a postmenopausal woman with receptorpositive breast cancer includes an aromatase inhibitor as initial therapy or after treatment with tamoxifen. Women with breast cancer and their physicians must weigh the risks and benefits of all therapeutic options.” Winer, et al JCO 2004 The Debate What is the Optimal Approach to the Use of an AI in the Adjuvant Setting? • Upfront AI x 5 years – Proponents of an upfront AI cite early benefit and seek to minimize risk of early relapse, hoping this will lead to longterm benefit • Tamoxifen x 2 years followed by AI x 3-5 years – Proponents of cross-over approach seek to minimize risk of late recurrence by using two effective agents, hoping that short-term losses will be more than compensated by longterm gains BIG 1-98: Design S U R G E R Y R R A A N N D D O O M Stratify M I I Institution Z Z E CT (Adjuvant/ E Neoadjuvant) -Prior -None -Concurrent R A N D O M I Z E 2-Arm Option A Tamoxifen N=911 B Letrozole N=917 N=1,828 Enrolled 1998-2000 4-Arm Option N=8,010* A Tamoxifen N=1548 B Letrozole N=1546 C Tamoxifen Letrozole N=1548 Letrozole Tamoxifen N=1540 D 0 2 Years N=6,182 Enrolled 1999-2003 5 Previous Analyses: Is 5 years Let superior to 5 years Tam as initial therapy? • Primary Core Analysis (PCA), Median follow-up 26 months • Monotherapy Arm Analysis, Median follow-up 51 months *ITT: excludes 18 patients who withdrew consent and did not receive study treatment Summary of Previous Analyses The PCA and monotherapy analyses showed that 5 years upfront letrozole is significantly superior to 5 years of upfront tamoxifen in terms of: – Disease-free survival – Time to distant recurrence BIG 1-98 Collaborative Group, N Engl J Med 2005;353:2747-57 Coates et al, J Clin Oncol 2007;25:486-92 BIG 1-98 Monotherapy Update Median Follow-up 76 months *Let:Tam: breast cancer events, 321:363 second (non breast) malignancy, 101:115 deaths without prior cancer event, 87:87 Mouridsen HT, et al: SABCS 2008, Abstr. 13 BIG 1-98 Sequential Treatment Disease-Free Survival Mouridsen HT, et al: SABCS 2008, Abstr. 13 Sequential Treatment Comparisons Median Follow-up 71 months Tam→Let vs. Let Let→Tam vs. Let Mouridsen HT, et al: SABCS 2008, Abstr. 13 Breast Cancer Events TamLet vs. Let Overall By Nodal Status* *42% of the population is node positive; 58% node negative Mouridsen HT, et al: SABCS 2008, Abstr. 13 Breast Cancer Events LetTam vs. Let Overall By Nodal Status* *42% of the population is node positive; 58% node negative Mouridsen HT, et al: SABCS 2008, Abstr. 13 Conclusions For postmenopausal women with endocrine-responsive breast cancer • Updated results of BIG 1-98 suggest superior overall survival with letrozole compared with tamoxifen • Adjuvant endocrine therapy should start with letrozole especially for patients at higher risk for early recurrence • Patients commenced on letrozole can be switched after 2 years to tamoxifen, if required • Safety is consistent with known safety profiles of each agent (data not shown) • Improved therapeutic approaches beyond five years are required to control late relapses Mouridsen HT, et al: SABCS 2008, Abstr. 13 Duration of Therapy The Natural History of HR+ Breast Cancer is Very Long • ER+ tumors demonstrate a relatively constant hazard of regression over time • After TAM x 5 years, over half of all recurrences occur in years 6-15 (EBCTCG, Lancet 2005) • MA-17: risk of recurrence was approx 2-3% each year on placebo arm (Ingle, SABCS 2005) • With 5-8 years follow-up, none of the AI trials are truly mature Saphner et al, JCO 1996 ATTom Results 2008 Gray et al, ASCO 2008 How Long Should AI Be Administered If Started After Tamoxifen? • No direct evidence for more than 2-3 years of an AI after a 2-3 years of tamoxifen, BUT… – In MA-17, a 5 year course of an AI is safe and data through 4 years of follow-up demonstrate ongoing effectiveness – In IES, benefit of E over T appears to be largely while patients are on treatment • Given these data, a 5 year course of AI treatment is reasonable when switching to AI after 2-3 years of tamoxifen Ongoing Studies to Establish Optimal Duration of AI Therapy: MA.17R AI x 5y Tam x 2y Letrozole x 5y AI x 5y Placebo x 5y Tamoxifen x 5y Letrozole x 5y Ongoing Studies to Establish Optimal Duration of AI Therapy > 10,000 pts will be studied – NSABP B42 • Letrozole vs placebo; N = 3,800 – SALSA • Anastrazole 2y vs 5y; N = 3,500 – SOLE • 5y continuous vs intermittent letrozole – Dutch • Anastrazole 3y vs 6y, N = 1,800 – GIM4 • Letrozole 2y vs letrozole 5y; N = 4,000 Can we identify which tumors and which patients will benefit most from the different strategies at our disposal? Heterogeneity of ER+ Breast Cancer Tumors Patients • HER2 status • Variability in drug metabolism • PR status • Grade • Luminal A vs B, or other genetic signature – CYP2D6 • Risk of toxicity • …and more • …and more And the lists will grow much longer in the years ahead Risk of Distant Recurrence Using Oncotype DX (21-Gene RS) in Patients Treated with Anastrozole or Tamoxifen: ATTAC Study • Objective was to evaluate the prognostic ability of 21-gene RS assay in patients treated in ATAC study • RS score was predictive of risk of recurrence in postmenopausal patients with ER+ with either node negative or node positive disease being treated with either tamoxifen or anastrozole Rate of Distant Recurrence at 9 Years Population N Low RS Intermediate RS High RS Lymph Node Negative 872 4% 10% 22% • Tamoxifen 432 3% 10% 30% • Anastrozole 440 4% 11% 12% Lymph Node Positive 306 16% 27% 46% • Tamoxifen 152 14% 28% 42% • Anastrozole 154 17% 25% 50% Dowsett et al. SABCS 2008, Abstract 53 CYP2D6 and Tamoxifen Pharmacogenetics CYP2D6 and Tamoxifen Metabolism Goetz, M. P. et al. J Clin Oncol; 23:9312-9318 2005 CYP2D6 and Tamoxifen Metabolism CYP2D6 Polymorphism Jin, JNCI 2005 Concomitant Drug Use and CYP2D6 Jin, JNCI 2005 Clinical Evidence Tamoxifen Pharmacogenetics and Clinical Outcomes DFS OS Goetz, et al JCO 2005 Clinical Evidence Tamoxifen Pharmacogenetics and Clinical Outcomes Goetz, et al JCO 2005 AI Toxicities • Arthralgias • Sexual Dysfunction • Osteoporosis AI Toxicities TEAM Trial Jones, S. E. et al. J Clin Oncol; 25:4765-4771 2007 AI Trials Summary Trial Timing Comparison HRQOL Endocrine Symptom ATAC Post surg A vs. T No effect Vag dryness, sexual dysfunction TEAM Post surg E vs. T NA Vag dryness, bone/muscle aches IES >2-3 Tam yrs E vs. T No effect --- No effect Vasomotor symptoms, bodily pain, sexual dysfunction MA.17 > 5 yrs Tam L vs. Pl From Whalen, 2006 Vaginal Estrogens for Genitourinary Symptoms Related to AI Therapy • Common complaint in postmenopausal women; aggravated by estrogen deprivation of AI • Topical / intravaginal estrogens may alleviate sx • Are they safe? • Kendall, SABCS 2005: E2 levels in women receiving concurrent AI treatment and Vagifem 25 mg PV BIW Estradiol Levels AI LET LET LET ANA BL <3 <3 3.5 <3 Day 14 220 232 77 46 Day 28 40 31 16 2.4 AI Arthralgia Syndrome Common complaint • Symmetric • Hands, feet, pelvis/hip, arms • Pathognomonic criteria: – “I aged overnight.” “I feel like an old lady.” – Squeezing hands/joints gesture • Etiology unclear ATAC Arthralgia Incidence over Time Sestak, et al. Lancet Oncology 2008 Diagnosis: AI-associated Joint Symptoms Pts referred to rheumatology at Michigan and Hopkins Diagnosis Bursitis Trochanteric Number of patients (%) 8 (21.1%) 6 (15.8%) Carpal tunnel syndrome 8 (21.1%) Osteoarthritis 11 (28.9%) Knee 3 (7.9%) Hand 2 (5.3%) Tendonitis 14 (36.8%) Rotator cuff/shoulder 8 (21.2%) Wrist 3 (7.9%) Elbow 2 (5.3%) Patellofemoral syndrome 7 (18.4%) AI Arthralgia Syndrome Practical Suggestions 1. Alert patients to this side effect 2. Reassure patients that this is not associated with destructive arthritis and that most cases are mild and abate over time 3. Encourage weight reduction and regular exercise 4. For more severely affected patients, suggest AI withdrawal to gauge relationship to treatment 5. Options: tamoxifen, other AIs, none Fracture Rates in Adjuvant AI Trials Aromatase Tamoxifen / Inhibitor Placebo ATAC 340 (11%) BIG 1-98 IES ABCSG/ ARNO MA.17 % Increase Reference 237 (7.7%) 43% Howell et al 2005 228 (5.8%) 162 (4.1%) 41% Thurlimann et al 2005 162 (7.0%) 111 (4.9%) 45% Coombes et al 2006 34 (2.0%) 16 (1.0%) 113% Jakesz et al 2005 137 (5.3%) 119 (4.6%) 15% Perez et al 2006 Influence of Different AI Strategies on BMD % change In BMD from baseline 4 3 2 1 0 -1 -2 -3 -4 -5 -6 -7 -8 x ATAC x x IES MA-17 x 0 1 2 3 4 Anastrazole (ATAC) Exemestane (IES) Tamoxifen (ATAC) Tamoxifen (IES) 5 x x 6 7 Years x Placebo (MA-17) x Letrozole (MA-17) Coleman et al Lancet Oncology 2007 ATAC: Annual Bone Fracture Rates ATAC Trialists, Lancet Oncology 2008;9:45 Bone Health Guidelines • Consider bone health when choosing adjuvant endocrine therapies • Check BMD at baseline when initiating AI therapy • Recheck BMD at 1-2 years • Initiate therapy for osteporosis / osteopenia according to standard guidelines derived from normal postmenopausal patient experience • Interventions that “work” in general population with osteopenia / osteoporosis also work in breast cancer survivors Case 2 • Premenopausal Women, 35 years old – T = 1.5 cm – ER+ – PR+ – HER2 negative – Grade 2 – LVI+ • Which patients with ER+ tumors should receive adjuvant chemotherapy? Case 2 Optimizing Therapy in Premenopausal Women Q: Which patients with ER+ breast cancer should receive chemotherapy? A: Those patients… • where tumor is not eradicated by surgery, or radiation, or adjuvant endocrine therapy, and • where tumor is sensitive to chemotherapy, and • where the patient is not likely to suffer gravely from other medical conditions before breast cancer recurrence, and • where the realistic benefits outweigh the risks of chemotherapy. The Dilemma Just exactly who are those patients? Current Recommendations for Chemotherapy for ER+ Breast Cancer NIH Consensus Conference 2000 • LN+ • LN – if T > 1 cm NCCN 2006 • LN+ • LN – if T > 1cm • Consider for LN – if 0.6 to 1.0 cm St. Gallen 2005 (endocrine responsive) • LN + (>4 LN if HER2 negative, any if HER2+) • Consider for LN – if: T > 2 cm, or grade 2-3, or LVI+, or HER2+, or age < 35 years Why Not Just Give Chemotherapy to Everyone? • Early Breast Cancer Trialists’ Group overview suggests benefit for chemotherapy irrespective of ER status, tamoxifen treatment, nodal status, or age • Landmark trials show benefit of chemotherapy for women with breast cancer compared to tamoxifen alone – Postmenopausal node positive (SWOG 8814) – Pre/postmenopausal node negative (NSABP B-20) • 2nd / 3rd generation trials of optimal chemotherapy show gains in outcome for ER+ and ER- tumors Why Not Just Give Chemotherapy to Everyone? The studies have major limitations that affect their application to patients in 2000 1. Chemotherapy-induced amenorrhea 2. Treatment regimens not contemporary e.g. chemotherapy without endocrine therapy 3. ER status positive vs negative vs low/poor vs missing 4. Patient age 5. Absolute vs. relative benefit Why Not Just Give Chemotherapy to Everyone? The studies have major limitations that affect their application to patients in 2006 1. Evolving taxonomy of breast cancer Biological subsets of breast cancer defined by pathological markers or gene expression arrays 2. Quantitative levels of ER / PR 3. Introduction of HEr testing and anti-HER2 therapy 4. Neoadjuvant chemotherapy studies demonstrate lower chance of pCR in ER+ in patients 5. Lack of molecular predictors for chemotherapy benefit Clinical Breast Cancer Subsets ER+ 65-75% All Breast Cancer HER2+ 15-20% Basaloid 15% Adjuvant Treatment for a 2 x 2 Marker Model of Breast Cancer HER2+ ER + ER -- Trastuzumab Chemo Trastuzumab Chemo Endocrine Endocrine HER2 - ± Chemo Chemo Candidate Gene Selection From ~40,000 genes 384 cancer-related genes* *Sources include: 1) Sotiriou et al., Breast Cancer Res Treat 4:R3, 2002 2) Scherf et al., Nat Genetics 24:236-44, 2000 3) Lamendola et al., Cancer Res 63:2200-5, 2003 4) Chang et al., Lancet 362:362-9, 2003 5) Staunton et al., Proc Natl Acad Sci U S A 98:10787-92, 2001 16 Cancer and 5 Reference Genes ESTROGEN PROLIFERATION Best RT-PCR performance and most robust predictions Ki-67 STK15 Survivin Cyclin B1 MYBL2 GSTM1 HER2 CD68 GRB7 HER2 BAG1 ER PR Bcl2 SCUBE2 INVASION Stromolysin 3 Cathepsin L2 REFERENCE Beta-actin GAPDH RPLPO GUS TFRC Single Gene Analysis in ER+, Tam+ Patients from Multiple Studies The Recurrence Score (RS) • The recurrence score unscaled is defined as: RSu= 0.47 x HER2 Group Threshold Score – 0.34 x ER Group Score + 1.04 x Proliferation Group Threshold Score + 0.10 x Invasion Group Score + 0.05 x CD68 – 0.08 x GSTM1 – 0.07 x BAG1 • Then the RSu is rescaled to be between 0 and 100: RS=(Rsu-6.7) x 20 and If RS<0, then RS=0; If RS>100, then RS=100. • Classification into three groups: Low risk group: Intermediate risk group: High risk group: if RS<18; if 18≤RS<31; if RS≥31. Genomic Health-NSABP B-14 Prospective Clinical Validation Study • Objective – Validate Recurrence Score as predictor of distant recurrence in N-, ER+, Tamoxifen-treated patients • Design – Pre-specified 21 gene assay, algorithm, endpoints, analysis plan – Blinded laboratory analysis of three 10 micron tumor block sections B-14 Placebo--Not Eligible Randomized Registered Tamoxifen--Eligible Tamoxifen--Eligible B14-Results DRFS - All 668 Patients 100% 90% 80% 70% 10 year DRFS = 85% 60% 50% DRFS 40% 30% 20% 10% 0% 0 2 4 6 8 Years 10 12 14 16 Oncotype DX™ Validation Study B-14 Rates of Distant Recurrence at 10 Years by RS Risk Category Paik et al. NEJM 2004;351:2817 Oncotype DX™ NSABP B-14: RS Subgroups by Patient Age All patients (N = 668) All Pts 59 Age <40 Age 40–50 Low Risk (RS <18) Int Risk (RS 18-30) High Risk (RS ≥31) 16 10 33 135 66 29 40 Age 50–60 Age >60 173 81 48 44 301 175 62 64 40% 60% 80% 100% % Distant Recurrence-free at 10 Years Oncotype DX™ NSABP B-14: RS Subgroups by Tumor Grade All Patients N = 668 Well 224 166 41 17 Moderate 296 139 80 77 Poor 148 33 28 87 All Pts Low Risk (RS<18) Int Risk (RS 18-31) High Risk (RS≥31) 20% 40% 60% 80% 100% % Distant Recurrence-free at 10 Years Recurrence Score and HER2 Status HER2 Status RS Result FISH + FISH - Low 0 334 Intermediate 5 142 High 50 129 Recurrence Score as a Continuous Predictor 40% Intermediate Risk Group Distant Recurrence at 10 Years Low Risk Group 35% High Risk Group 30% 25% 20% 15% 10% 5% 95% CI 0% 0 5 10 15 20 25 30 Recurrence Score 35 40 45 50 Recurrence Score as a Continuous Predictor 40% Intermediate Risk Group Low Risk Group Distant Recurrence at 10 Years 35% High Risk Group My RS is 30, What is the chance of recurrence within 10 yrs? 30% 25% 20% 15% 10% 5% 95% CI 0% 0 5 10 15 20 25 30 Recurrence Score 35 40 45 50 Chemotherapy Response and Oncotype DX NSABP Study B-20 Design: Tam + MF Randomized Tam + CMF Tam Objective: Determine the magnitude of the chemotherapy benefit as a function of 21 gene Recurrence Score assay NSABP B-20 Outcome by Recurrence Score Overall Int risk 18-30 Low risk < 18 High risk > 30 Paik, S. et al. J Clin Oncol; 24:3726-3734 2006 Linear fit of Distant Recurrence as a Continuous Function of RS for TAM and TAM + Chemo Paik, S. et al. J Clin Oncol; 24:3726-3734 2006 1.00 Disease-Free Survival by Treatment Disease-free survival 0.25 0.50 0.75 SWOG 8814 Postmeno, ER+, LN+ Tam ± CAF Stratified log-rank p = 0.97 at 10 years Tamoxifen (n=55, 15 events) CAF-T (n=91, 26 events) 0.00 Albain, et al. SABCS 2007 Low risk (RS < 18) 0 2 4 6 8 10 Disease-Free Survival by Treatment Disease-Free Survival by Treatment 1.00 1.00 0.25 Stratified log-rank p = 0.033 at 10 years 0 2 4 6 Years since registration 8 0.75 0.50 Stratified log-rank p = 0.48 at 10 years Tamoxifen CAF-T 0.00 Tamoxifen (n=47, 26 events) CAF-T (n=71, 28 events) Intermediate risk (RS 18-30) 0.25 0.50 0.75 Disease-free survival High risk (RS ≥31) 0.00 Disease-free survival Years since registration 10 0 2 4 (n=46, 22 events) (n=57, 20 events) 6 Years since registration 8 10 TAILORx Sparano, J. A. et al. J Clin Oncol; 26:721-728 2008 Genomic Health-NSABP B-14 Prospective Clinical Validation Study • Objective – Validate Recurrence Score as predictor of distant recurrence in N-, ER+, Tamoxifen-treated patients • Design Placebo--Not Eligible B-14 Randomized Tamoxifen--Eligible Registered Tamoxifen--Eligible •Pre-specified 21 gene assay, algorithm, endpoints, analysis plan •Blinded laboratory analysis of three 10 micron tumor block sections Benefit from Tamoxifen in the NSABP B14 1.0 0.8 0.8 0.6 0.6 0.4 DRFS 1.0 Low Risk (RS<18) 0.2 Placebo Tamoxifen N 171 142 0.0 0 2 4 6 0.4 Int Risk (RS 18-30) N 85 Placebo Tamoxifen 69 0.2 8 12 10 Years 14 0.0 16 0 2 4 1.0 6 8 Years 0.8 DRFS DRFS by Oncotype DX Recurrence Score 0.6 0.4 High Risk (RS≥31) 0.2 Placebo Tamoxifen N 99 79 0.0 0 2 4 6 8 Years 10 12 14 16 10 12 14 16 How Many Genomic Assays Do We Need? Multi-gene Arrays and Prediction of DFS in Cohort of ER+ Breast Cancer Fan C et al. N Engl J Med 2006; 355:560-569 ASCO Tumor Marker Panel Multiparameter Gene Expression Analysis for Breast Cancer • Oncotype DX™ can be used to determine prognosis in newly diagnosed patients with node-negative, estrogen-receptor positive breast cancer who will receive tamoxifen. Indications: – To predict risk of recurrence in patients considering treatment with tamoxifen – To identify patients who are predicted to obtain the most therapeutic benefit from adjuvant tamoxifen and may not require adjuvant chemotherapy – Patients with high recurrence scores appear to achieve relatively more benefit from adjuvant chemotherapy (specifically CMF) than from tamoxifen • Conclusions may not be generalizable to hormonal therapies other than tamoxifen, or to other chemotherapy regimens. • Several other multi-parameter assays have been reported and a few are commercially available, including Mammaprint and the Rotterdam Signature. However, the Committee felt that the precise clinical utility and appropriate application for these other assays were insufficiently defined to recommend their use. ASCO 2007; available at http://jco.ascopubs.org/cgi/content/full/25/33/5287 Case 2 Summary Optimizing Therapy in Premenopausal Women • Traditional criteria for recommending chemotherapy in ER+ breast cancer relate to risk of recurrence, not chemotherapy sensitivity – T, N stage – Age • Chemotherapy benefits vary from tumor to tumor, and thus patient to patient • Genomic assays can inform the likelihood of sensitivity to chemotherapy Clinical Updates Hormonally Sensitive, Early-Stage Breast Cancer Current Considerations in the Management of Patients with Hormonally Sensitive Early-stage Breast Cancer Concluding Remarks