Advances in Breast Cancer Treatment: anti-her2 Therapy, PARP inhibitors, and Immunotherapy

Transcription

1 Advances in Breast Cancer Treatment: anti-her2 Therapy, PARP inhibitors, and Immunotherapy ASCO Highlights Oklahoma Society of Clinical Oncology Sarah S. Mougalian, MD Assistant Professor of Medicine Yale Cancer Center Section of Breast Medical Oncology August 19, 2017 S L I D E 0

2 Disclosures Research Funding: NCCN/Pfizer, Genentech Consulting Fees: Eisai, Inc. S L I D E 1

3 Outline Adjuvant HER2-Based Therapy APHINITY (von Minckwitz et al) Update on the APT Trial (Tolaney et al) Olaparib for patients with mbc and germline BRCA mutations (Robson et al) PD-1 inhibitors in Breast Cancer: Pembrolizumab KEYNOTE-086 (Adams et al) ISPY-2 (Nanda et al) Patient-Reported Outcomes (Basch et al) S L I D E 2

4 Adjuvant Treatment of HER2- positive Breast Cancer: More or Less? S L I D E 3

5 Background: APHINITY Adding pertuzumab to trastuzumab with chemotherapy: APHINITY Pertuzumab has complementary mechanisms of action with trastuzumab In the metastatic setting, pertuzumab added to trastuzumab and docetaxel significantly improved PFS and OS Addition of pertuzumab to trastuzumab-containing chemotherapy improves pcr Should we extend the use of pertuzumab into the adjuvant setting for all patients with HER2 positive breast cancer? S L I D E 4

6 APHINITY (Adjuvant Pertuzumab and Herceptin in Initial Therapy) S L I D E 5

7 Surgery APHINITY TRIAL SCHEMA 4805 Patients Centrally Confirmed HER2 positive disease (IHC 3+ or FISH/CISH+) R Chemotherapy* + trastuzumab + pertuzumab Chemotherapy* + trastuzumab + placebo Follow Up 10 Years Randomization and treatment within 8 weeks of surgery Eligibility: Node-positive, any T except T0 T 1cm, OR If T >0.5cm and <1cm, must have grade 3, ER/PR neg, and/or age <35 Baseline EF 55% Anti-HER2 therapy for a total of 1 year, concurrent with start of taxane *Several standard third generation or nonanthracycline regimens were allowed Primary Endpoint: Invasive Disease-Free Survival Statistical Assumptions: HR 0.75 (89.2% vs 91.8%,Δ =2.6%) S L I D E 6

8 Demographic and Baseline Disease Characteristics of the Patients. ~62% von Minckwitz G et al. N Engl J Med DOI: /NEJMoa S L I D E 7

9 Primary Endpoint Analysis: Invasive DFS Δ=0.9% NNT: 112 (overall) Δ=1.7% at 4 years von Minckwitz G et al. N Engl J Med DOI: /NEJMoa S L I D E 8

10 Site of First Invasive-Disease Event. Δ=1.1% Δ=0.1% von Minckwitz G et al. N Engl J Med DOI: /NEJMoa S L I D E 9

11 Invasive-Disease free Survival: NODE POSITIVE Δ=1.8% NNT: 56 Δ=3.2% at 4 years von Minckwitz G et al. N Engl J Med DOI: /NEJMoa S L I D E 10

12 Invasive-Disease free Survival: NODE NEGATIVE No Difference von Minckwitz G et al. N Engl J Med DOI: /NEJMoa S L I D E 11

13 Invasive-Disease free Survival: HR NEGATIVE Δ=1.6% NNT: 63 Δ=2.3% at 4 years S L I D E 12

14 Invasive-Disease free Survival: HR POSITIVE No Difference S L I D E 13

15 Summary of Adverse Events (Safety Analysis Population). All grades: 71.2% vs. 45.2% Not statistically significantly different von Minckwitz G et al. N Engl J Med DOI: /NEJMoa S L I D E 14

16 Seven-year follow-up of adjuvant paclitaxel and trastuzumab (APT Trial) for node-negative, HER2+ Breast Cancer Sara M. Tolaney, William T. Barry, Hao Guo, Deborah A. Dillon, Chau T. Dang, Denise A. Yardley, Beverly Moy, P. Kelly Marcom, Kathy S. Albain, Hope S. Rugo, Matthew Ellis, Iuliana Shapira, Antonio C. Wolff, Lisa A. Carey, Beth A. Overmoyer, Ann H. Partridge, Clifford A. Hudis, Ian E. Krop, Harold J. Burstein, Eric P. Winer

17 Background: The APT Trial De-escalating chemotherapy in small HER2 positive breast cancers Retrospective data suggest that patients with small HER2+ breast cancer have more than just a minimal risk of disease recurrence Majority of pivotal adjuvant trials excluded these patients APT was designed to address treatment for this patient population S L I D E 16

18 APT: Study Design HER2+ ER+ or ER- Node Negative < 3 cm P P P P P P P P P P P P Enroll T T T T T T T T T T T T WEEKLY PACLITAXEL 80 mg/m 2 + TRASTUZUMAB 2 mg/kg x 12 N=410 T T T T T T T T T T T T T FOLLOWED BY 13 EVERY 3 WEEK DOSES OF TRASTUZUMAB (6 mg/kg)* Presented by: Sara M. Tolaney

19 Study History 410 patients enrolled 10/2007-9/ patients received treatment Results published NEJM 2015: 3 yr DFS 98.7% (95% CI: ) 12 DFS events seen (including 2 distant recurrences) Current analysis is with all data available as of Nov 2016 and includes 2390 patient years of follow-up Presented by:

20 Patient Characteristics Age < Size of Primary Tumor T1a 0.5 cm T1b > T1c > T2 > Histologic Grade I Well differentiated II Moderately differentiated III Poorly differentiated HR Status (ER and/or PR) Positive Negative Median age: 55 91% T 2cm N % Presented by:

21 Disease-Free Survival Disease-Free Survival N = % HR-positive 91% T 2cm 98.5% N0 5.9 years/pt (total follow up: 2,390 patient-years) Point Est. 95% Conf. Interval No. of events 3-yr DFS 98.5% 97.2% to 99.7% 6 5-yr DFS 96.3% 94.4% to 98.2% 14 7-yr DFS 93.3% 90.4% to 96.2% 23 All patients Time (Months) Number at risk Presented by:

22 Disease-Free Survival Events DFS Event N (%) Time to event [months; mean(range)] Any recurrence or death 23 (5.7) Local/Regional Recurrence* Ipsilateral axilla (HER2+) Ipsilateral breast (HER2+) New Contralateral Primary Breast Cancer HER2+ HER2- Unknown 5 (1.2) (1.5) (12-54) 51 (37-65) (12-59) 87 (84-90) Distant Recurrence 4 (1.0) 49 (27-63) Death Non-breast cancer related 8 (2.0) 58 (13-71) Presented by:

23 Disease-Free Survival Disease-Free Survival by HR status Stratum No. of events 7-yr DFS 95% Conf. Interval Negative % 84.6% to 97.2% Positive % 91.8% to 97.5% neg pos Time (Months) Number at risk Presented by:

24 Take Home Points Both studies demonstrated excellent outcomes APHINITY met its primary objective; 0.9% IDFS at 3 years (1.7% at 4 years) Treatment effect more pronounced in node-positive (3.2% benefit at 4 years) and HR-negative (2.3% benefit at 4 years) subgroups No difference in cardiac toxicity Diarrhea was much more frequent in pertuzumab arm REGIMEN Cost (USD) Diff from 1yr Trastuzumab Trastuzumab (1yr) $55,908 - Tras + Pertuzumab $150,504 + $94,596 The regimen of weekly Taxol x 12 with one year of trastuzumab has excellent outcomes With a median follow-up of 6.5 years, the 7-yr DFS was 93.3%, with just 4 distant recurrences Financial data adapted from oral presentation from CK Anders, ASCO 2017 S L I D E 23

25 So what is a reasonable approach? For older women with stage I HER2 positive cancers, particularly when HR positive: For cancers <2cm, particularly when HR positive, consider weekly paclitaxel x 12 with one year of trastuzumab Not likely to find out how TH compares to regimens containing combination chemotherapy (e.g. TCH) Consider the addition of pertuzumab in high risk HER2 positive patients (e.g. Node positive and/or ER/PR negative) More diarrhea; no difference in cardiac outcomes Substantially higher cost S L I D E 24

26 PARP Inhibitors in patients with germline BRCA mutations S L I D E 25

27 OlympiAD: Phase III trial of olaparib monotherapy versus chemotherapy for patients with HER2 negative metastatic breast cancer and a germline BRCA mutation S L I D E 26

28 Background Approximately 5% of patients with breast cancer harbor a germline mutation in BRCA1 and/or BRCA2 BRCA1 and BRCA2 are tumor suppressor genes involved in in homologous recombination repair of dsdna breaks PARP1 and PARP2 are involved in the cellular response to singlestrand DNA breaks Inhibition of PARP results in trapping of the protein on DNA, inhibiting replication fork progression and increasing dsdna breaks Resolution of lesions caused by PARP inhibition relies on functional homologous recombination Cells lacking BRCA1/2 are sensitive to PARP inhibition in vitro Olaparib is an oral PARP inhibitor that is FDA approved for the treatment of BRCA-associated ovarian cancer (3+ prior chemotherapy treatments) S L I D E 27

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32 Olaparib 300mg BID (N=205) Chemotherapy TPC (N=97) Age, years (median, range) 44 (22-76) 45 (24-68) White race, n (%) 134 (66) 64 (65) BRCA mutation status, n (%) BRCA1 BRCA2 Both Hormonal receptor status, n (%) ER+ and/or PR+ TNBC 117 (57) 84 (41) 4 (2) 103 (50) 102 (50) 51 (53) 46 (47) 0 49 (51) 48 (49) Prior chemotherapy for metastasis, n (%) 148 (71) 69 (71) Prior platinum treatment, n (%) 60 (29) 26 (27) De novo metastatic breast cancer 26 (13) 12 (12) Prior lines of chemotherapy for metastases (33) 80 (39) 57 (28) 31 (32) 42 (43) 24 (25) Chemotherapy TPC* Capecitabine Eribulin Vinorelbine N/A 41 (45) 34 (37) 16 (18) S L I D E 31

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36 Response Rates 100 of 167 patients who had measurable disease in the olaparib group had a response to treatment (59.9%) Compared to 19 of 66 patients in standard therapy arm (28.8%) CR in 9.0% of patients in olaparib group (1.5% in standard group) Median duration of response 6.4 months in olaparib arm and 7.1 months in standard therapy arm Median time to response was similar (47 days and 45 days) Treatment duration was longer in olaparib arm (8.2 months) than chemotherapy arm (3.4 months) S L I D E 35

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40 Conclusions OlympiAD is the first phase III study in patients with mbc demonstrating benefit for a PARP inhibitor over an active comparator Olaparib monotherapy provided a statistically significant and clinically meaningful benefit in PFS when compared to standardof-care chemotherapy in patients with HER2 negative metastatic breast cancer and a germline BRCA mutation Response rates to olaparib were high (~60%), and time to response was similar to that achieved with chemotherapy Olaparib was generally well tolerated, with < 5% discontinuation for toxicity and lower rate of grade >3 AE s compared to chemotherapy S L I D E 39

41 Take Home Points Germline BRCA status now has implications for systemic treatment of metastatic breast cancer Olaparib likely to be FDA approved for this indication in coming months Veliparib, talazoparib currently being studied in this population Adjuvant breast trials are underway (OlympiA) Important to engage in guideline-concordant genetic testing Results may be driven by platinum-naïve, triple negative cancers Need further study of subgroups to understand who benefits Consider use of olaparib in women with germline BRCA mutations after progression after front-line treatments Additional research needed before its use in earlier line settings S L I D E 40

42 Immune Checkpoint Inhibitors in Breast Cancer: Pembrolizumab S L I D E 41

43 Background TNBC: aggressive, heterogeneous breast cancer subtype with a high unmet need Standard of care is cytotoxic chemotherapy, but median overall survival is poor (~12 months) Pembrolizumab is a humanized monoclonal antibody against PD-1 that provides dual ligand blockade of PD-L1 and PD-L2 Durable antitumor activity and manageable safety in PD-L1-positive mtnbc in phase 1 trials (KEYNOTE-012) S L I D E 42

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45 Phase II, multicohort, single-arm estimation study Open to patients regardless of PD-L1 expression 27 weeks on trial

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48 Overall response rate: 1 CR, 7 PR Disease control rate: incl 5 SD 24 weeks

49 No difference in response rate between PD-L1 positive and PD- L1 negative cohorts, although there were slightly more patients with stable disease in the PD-L1 cohort

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53 Pembrolizumab plus standard neoadjuvant therapy for high-risk breast cancer: Results from the I-SPY 2 Trial Rita Nanda, Minetta C. Liu, Douglas Yee, Angela M. DeMichele, Christina Yau, Smita M. Asare, Nola M. Hylton, Laura J. van t Veer, Jane Perlmutter, Anne M. Wallace, A. Jo Chien, Andres Forero-Torres, Erin D. Ellis, Heather S. Han, Amy S. Clark, Kathy S. Albain, Judy C. Boughey, Anthony D. Elias, Claudine Isaacs, Kathleen Kemmer, Hope S. Rugo, Michelle Melisko, Fraser Symmans, Donald A. Berry, Laura J. Esserman, I-SPY 2 TRIAL Investigators. This presentation is the intellectual property of I-SPY. Contact rnanda@medicine.bsd.uchicago.edu for permission to reprint and/or distribute.

54 The I-SPY 2 TRIAL Standing Platform Phase II, adaptively-randomized neoadjuvant trial Goal: efficiently identify promising agents to take to phase III Multiple concurrent experimental arms; 13 agents to date Adaptive randomization minimizes number of patients needed to determine efficacy Information from MRIs and surgeries feeds back into the model to increase the likelihood that patients are randomized to more effective therapies Graduation for efficacy = reach an 85% predicted probability of success in a 1:1 randomized 300 patient phase III trial Not every drug graduates (can be dropped for futility/toxicity or reach maximum accrual) Generates estimated pcr rate and predictive probability distributions of pcr rates by signature Actual pcr rates are not reported, as they are biased by the adaptive randomization) This arm of the I-SPY 2 Trial tested whether of the addition of pembrolizumab improves pathologic complete response (pcr) rates over standard therapy 53

55 I-SPY 2 TRIAL Eligibility Screening Consent Assess Eligibility Core Biopsy Tumor size > 2.5 cm Candidate for preoperative chemotherapy Study MRI and biopsy MammaPrint (MP) Adequate organ function, PS<2 HER2+ (IHC, FISH, TargetPrint) Triple negative HR+, MP High Risk Randomized Consented to Assigned Arm ELIGIBLE 54

56 Primary Endpoint: pcr Defined as no residual invasive cancer in the breast or lymph nodes (ypt0/is and ypn0) Intent-to-treat Protocol-defined non-pcr: Switch to non-protocol assigned therapy (e.g. addition of carbo) No surgery Withdrawal from the trial Pembrolizumab was studied in 3 HER2 negative biomarker signatures All HER2- HR+/HER2- HR-/HER2- (triple-negative breast cancer; TNBC) 55

57 I-SPY 2 TRIAL Schema: HER2- Signatures Adaptive Randomization Paclitaxel Paclitaxel + Pembro Other HER2- Arms Doxorubicin 60 mg/m2 Cyclophosphamide 600 mg/m2 X 4 12 weeks 8-12 weeks S U R G E R Y Control Paclitaxel 80 mg/m2 every wk x 12 Experimental Paclitaxel 80 mg/m2 every wk x 12 Pembro 200 mg every 3 wks x 4 56

58 Demographics Patient Characteristic Pembrolizumab (n=69) Control (n=180) Median Age, yrs (range) 50 (27-71) 47 (22-77) Race, % White African American Asian Other HR Status, % Positive Negative Median tumor size, cm (range) Nodal Status Positive Negative Missing ( ) ( )

59 Pembrolizumab graduated in all HER2- signatures: Both HR+/HER2- and TN Signature All HER2- TNBC HR+/HER2- Estimated pcr rate (95% probabilty interval) Pembro 0.46 ( ) 0.60 ( ) 0.34 ( ) Control 0.16 ( ) 0.20 ( ) 0.13 ( ) Probability pembro is superior to control Predictive probability of success in phase 3 > 99% 99% >99% >99% >99% 88% The Bayesian model estimated pcr rates appropriately adjust to characteristics of the I-SPY 2 population. The raw pcr rates (not shown) are higher than the model estimate of in TNBC. 58

60 pcr Probability Distributions by Signature Curves: probability distribution of pcr rate Blue = control, Red = experimental Midpoint of curves: estimated pcr rate Separation: strength Width: certainty 59

61 Select treatment-related adverse events Pembrolizumab (n=69) % (n) Control (n=180) % (n) All grades Grades 3-5 All grades Grades 3-5 Febrile neutropenia 7.2 (5) 7.2 (5) 6.7 (12) 6.7 (12) Neutropenia w/o fever 5.8 (4) 1.4 (1) 1.7 (3) 0 (0) Anemia 27.5 (19) 4.3 (3) 18.9 (34) 3.9 (7) Fatigue 79.7 (55) 5.8 (4) 81.1 (146) 0.6 (1) Nausea 73.9 (51) 4.3 (3) 71.7 (129) 0 (0) Vomiting 34.8 (24) 1.4 (1) 18.3 (33) 0 (0) Diarrhea 49.3 (34) 7.2 (5) 37.8 (68) 2.2 (4) Peripheral motor neuropathy 13.0 (9) 1.4 (1) 4.4 (8) 0 (0) Peripheral sensory neuropathy From start of treatment to 30 days after surgery (3 months after last dose of pembrolizumab) Up to 60 days after treatment for those not undergoing surgery 50.7 (35) 1.4 (1) 59.4 (107) 1.1 (2) 60

62 Adverse Events of Special Interest (including immune-related toxicities) Pembrolizumab (n=69) % (n) Control (n=180) % (n) All grades Grade 3-5 All grades Grade 3-5 Hypothyroidism 8.7 (6) 1.4 (1) 0.6 (1) 0 (0) Hyperthyroidism 4.3 (3) 0 (0) 0 (0) 0 (0) Adrenal Insufficiency^ 8.7 (6) 7.2 (5) 0 (0) 0 (0) Hepatitis 2.9 (2) 2.9 (2) 0 (0) 0 (0) Pneumonitis 2.9 (2) 0 (0) 1.1 (2) 0.6 (1) Colitis 1.4 (1) 1.4 (1) 0.6 (1) 0.6 (1) Pruritis 24.6 (17) 0 (0) 11.1 (20) 0.6 (1) *includes both hyperthyroidism and hypothyroidism ^includes primary and secondary causes of AI 61

63 Primary and Secondary Adrenal Insufficiency Adrenal insufficiency reported in 6 patients At least 3 were related to hypophysitis (secondary AI) 5 presented after completion of AC (10-12 weeks after last pembro dose) 1 presented during pembro treatment (5 weeks after 1 st pembro dose) Variable presentation (N/V, fatigue, weakness) Patients on replacement therapy Primary and secondary AI are known toxicities of pembrolizumab Rates across all studies are 0.8% and 0.6% Due to the toxicities observed, serial screening AM cortisol levels have been incorporated into trial, in addition to ongoing serial thyroid function testing 62

64 KEYNOTE 173 (Schmid et al), ASCO 2017 S L I D E 63

65 Yale IIT (Pusztai et al), ASCO 2017 L Pusztai, PI S L I D E 64

66 Comparison of pcr rates in TNBC SWOG S0800 SWOG S0800 CALGB CALGB KEYNOTE-173 B KEYNOTE-173 A Yale Institutional IIT I-SPY2 Nab-paclitaxel with bevacizumab ddac Nab-paclitaxel ddac Paclitaxel + carboplatin ddac Paclitaxel ddac Nab-paclitaxel + carboplatin ddac with pembrolizumab Nab-paclitaxel ddac with pembrolizumab Nab-paclitaxel ddac with MEDI4736 (durvalumab) Paclitaxel ddac with pembrolizumab * No checkpoint inhibition 6/10 patients 8/10 patients 5/7 patients S L I D E 65

67 Take Home Points Immunotherapy is not ready for prime time in breast cancer yet Optimal agent(s), doses, concurrent cytotoxic chemo, sequence TBD There appears to be activity of anti PD-1 agent monotherapy, although with low rates of overall response and clinical benefit Activity may be greater in patients with less heavily pretreated disease Await results of biomarker/til analyses Generally quite well tolerated When used in combination with cytotoxic chemotherapy, pcr rates with anti PD-1 and anti PD-L1 agents are impressive Tripling of the estimated pcr rate in TNBC (60% vs 20%) Near-tripling of the estimated pcr rate in HR+/HER2- (34% vs 13%) Adrenal insufficiency was observed at a higher rate than previously reported in advanced cancer S L I D E 66

68 Impact of Patient-Reported Outcome Assessment on Survival S L I D E 67

69 Overall Survival Results of a Randomized Trial Assessing Patient-Reported Outcomes for Symptom Monitoring During Routine Cancer Treatment Symptoms are common in advanced cancer Interfere with daily activities Frequently lead to ER and hospital visits Symptom management is a cornerstone of high-quality oncology practice S L I D E 68

70 Current approach: REACTIVE Patient reports symptoms during office visit Limited time Competing topics Patient/clinician forget to communicate the symptoms Patients are reluctant to contact the office or have difficulty reaching appropriate office staff S L I D E 69

71 Systematic Symptom Monitoring: PROACTIVE Automatic reminders to patients by or text to report symptoms at regular intervals The system then alerts clinicians in real time regarding severe or worsening symptoms to trigger symptom management Generate reports showing trends over time Problems are addressed before they cause problems Interactions between patient and provider are more focused S L I D E 70

72 Hypothesis and Study Design Proactive symptom monitoring during chemotherapy will improve symptom management, leading to better clinical outcomes Patients receiving chemotherapy for metastatic breast, lung, GU, or GYN cancer at MSKCC R INTERVENTION ARM Self report 12 common symptoms Prior to / between visits, by web Weekly reminders to patients Alerts to nurses (by ) Reports to oncologists (at visits) CONTROL ARM Standard symptom monitoring OUTCOMES QOL (primary) ER Visits Survival Treatment discontinuation, withdrawal, hospice, death Web-based intervention Symptoms included: appetite loss, constipation, cough, diarrhea, dyspnea, dysuria, fatigue, hot flashes, nausea, pain, neuropathy, and vomiting, graded on a 5 point scale Patients received weekly reminder s to remind them to report S L I D E 71

73 Results 766 patients enrolled between June 2007 and January 2011 Overall survival analysis June 2016, median follow up 7 years, and 67% of participants had died Patients self-reported symptoms 73% of the time when prompted to do so Nurses took action in response to alerts 77% of the time Interventions included: counseling, supportive medications, referrals to ER, chemotherapy dose modifications, imaging S L I D E 72

74 Results QOL assessed at 6 months, compared to baseline Compared to standard care, 31% more patients in the self-reporting arms experienced QOL benefits Compared to standard care, 7% fewer patients in the self-reporting arm visited the ER S L I D E 73

75 Overall Survival Median Survival: Self-reporting arm: 31.2 months Standard care arm: 26.0 months Δ =5.2 months, p=0.03 Persisted on multivariable analysis (Adjusted HR 0.832, 95% CI ) S L I D E 74

76 Potential Mechanisms of Action Proactive monitoring prompts clinicians to intervene early, before symptoms worsen and cause serious downstream complications Nurses took action in response to most alerts (77%) Patients were kept out of the ER Symptom control enables patients to stay more functional, which is known to be associated with better survival Compared to standard care, self-reporting was associated with better physical functioning and self care Symptom monitoring improves control of chemotherapy side effects, enabling more intensive and longer duration of cancer treatment Compared to standard care, patients who self-reported were able to receive chemotherapy 2 months longer on average (6.3 months vs. 8.2 months) S L I D E 75

77 Limitations Single center trial Diverse population Results being further explored in national trial Study was powered to assess QOL Technology and e-health have evolved S L I D E 76

78 2016 FDA Approvals for Metastatic Solid Tumors Overall Survival Benefit (Months) Ofaratumab (Soft tissue sarcoma) Current Study Cabozantinib (RCC) Atezolizumab (NSCLC) Pembrolizumab (NSCLC) Atezolizumab (NSCLC) Nivolumab (SCCHN) Eribulin (liposarcoma) Adapted from And M. Krzyzanowska MD MPH FRCPC S L I D E 77

79 Take Home Points Systematic collection of PROs for ALL patients should be standard Must include interval collection of PROs between visits ACTIONABLE S L I D E 78

80 Thank You/Questions Drs. Von Minckwitz, Anders, Tolaney, Robson, Adams, Nanda, Basch, and Krzyzanowska for sharing their slides S L I D E 79