Late Recurrence and Death in ER Positive Early Stage Breast Cancer The Next Frontier. Daniel F. Hayes, MD, FASCO, FACP Breast Oncology Program

Transcription

1 Late Recurrence and Death in ER Positive Early Stage Breast Cancer The Next Frontier Daniel F. Hayes, MD, FASCO, FACP Breast Oncology Program

2 Conflicts of Interest Research Funding Menarini/Silicon Biosystems(Manufacturer of CellSearch) Astra-Zeneca Novartis Pfizer 2 patents regarding capture and characterization of CTCs One licensed to Menarini/Silicon Biosystems with royalties to DFH Stock Options (not relevant to this talk) OncImmune, InBiomotion

3 ER Positive Breast Cancer: Adjuvant Endocrine Therapy Principle #1 5 years of adjuvant ET decreases risk of recurrence and mortality in ER POS BrCa by 40-50% Tam vs. Nil AI vs. Tam Early Breast Cancer Trialists' Collaborative Group. Lancet. 365: , 2005 Dowsett, et al. Aromatase Inhibitor Overview Group, J Clin Oncol 28:509-18, 2010

4 ER Positive Breast Cancer: Adjuvant Endocrine Therapy Principle #2 The risk for recurrence of ER POS BrCa Is highest in first 4-6 years Never declines to zero, even as long as years after diagnosis

5 Oxford Overview (Early Breast Cancer Trialists Collaborative Group EBCTCG) Late Distant Recurrence and Mortality in Women with ER POS BrCa Who Were Assigned to Stop Endocrine Therapy at 5 Yrs Pan, Gray, Braybrooke, Davies, Taylor, McGale, Peto, Pritchard, Bergh, Dowsett, Hayes and EBCTCG N Engl J Med 377: , 2017

6 Distant Recurrence by Nodal Status & T Size Patients Without 5 Yrs; Years 5-20 Distant recurrence, % ET for 5 years T1 only 25% 15% 14% 7% 8% years No. at risk (and, in each 5-year period, no. of events and annual rate) T1N (391, 3.2%) 1193 (68, 2.6%) 214 (11, 2.2%) 32 T1N (734, 1.5%) 5138 (162, 1.5%) 817 (35, 1.7%) 154 T1N (509, 0.8%) 8020 (218, 1.0%) 2345 (58, 1.0%) 440 4% 4-9 POS NODES= 34% 34% T1N POS NODES= 20% 20% T1N1-3 0 POS NODES= 13% 13% T1N0 Distant recurrence, % T2 only 31% 20% 19% 11% 14% ET for 5 years 7% years No. at risk (and, in each 5-year period, no. of events and annual rate) T2N (688, 4.5%) 1517 (106, 3.3%) 285 (12, 1.7%) 51 T2N (842, 2.4%) 3551 (134, 1.8%) 614 (28, 1.9%) 114 T2N (512, 1.6%) 3901 (152, 1.4%) 1129 (37, 1.3%) POS NODES= 41% 41% T2N POS NODES= 26% 0 POS NODES= 19% 26% T2N1-3 19% T2N0 Pan et al NEJM 2017

7 Association of TN Status and grade with Distant Recurrence Table 1. Association of TN status and grade with distant recurrence risk in years 5-10 an ,923 women with T1/T2 N0-9 ER+ disease scheduled 5 years of adjuvant endocrine therapy (ET) and disease-free at year 5. All trends: P< Number of women event-free at year 5 Chemotherapy Total scheduled Annual rate (%) of distant recurrence Years Years Cumulative risk, years 5-20 (%) Nodal involvement N0 28,847 9,136 (32%) N1-3 25,292 17,280 (68%) N4-9 8,784 6,664 (76%) Diameter in mm, N0 only 10 (T1a/b) 5, (16%) (T1c) 13,875 4,034 (29%) (T2) 6,700 2,859 (43%) (T2) 2,745 1,333 (49%) Tumor grade, T1N0 only Low 3, (11%) Moderate 7,363 1,861 (25%) High (poorly differentiated) 3,054 1,414 (46%) Pan et al NEJM 2017

8 Conclusions: Late Recurrence in ER Pos Br Ca The risk of late distant recurrence and Br Ca mortality is relentless in women with ER POS Disease who stop ET at 5 years Annual rate is constant for at least 15 years After 5 years, the annual event rate is a function of original Nodal status Size Grade NOT: PgR, HER2, other factors Modern estimates may be less, tempered by: Observed better prognosis over last decade (TailoRx, RxPonder taking longer to report) Earlier diagnosis Better staging More effective ET, chemotherapy and anti-her2 therapies Other?

9 Principle #3 ER Positive Breast Cancer: Adjuvant Endocrine Therapy Extended ET beyond 5 years further reduces the risk of recurrence Tamoxifen after tamoxifen: ~ 1/3 reduction AI after tamoxifen: AI after AI: ~ 1/2 reduction Controversial

10 Extended TAMOXIFEN Reduces Recurrence and Death in ER POS Breast Cancer ATLAS TRIAL: Tamoxifen after ~ 5 Yrs of TAM Davies, et al., Lancet 381:805-16, 2013

11 Extended AI after 5 Years of Tam NCIC MA17 Letrozole NSABP B33 DFS HR= 0.37; p<.0001) ddfs HR= 0.39; p=.004) Placebo EFS HR= 0.44; p<.004) Goss et al. JNCI 97: , 2005 Mamounas, et al., J Clin Oncol 26: , 2008

12 Conclusions: Extended Adjuvant ET Most patients with ER POS BrCa should consider extended adjuvant ET Reduces risk by 1/3-1/2 after 5 years of tam Unclear if extended AI after ~ 5 or more years of AI is effective BUT..

13 Principle #4 ER Positive Breast Cancer: Extended Adjuvant Endocrine Therapy Most (80-90%) patients who have received 5 years of endocrine therapy without a recurrence are unlikely to die of metastatic BrCa And

14 Adjuvant ET has significant side effects Life changing/quality of Life Tamoxifen and Aromatase Inhibitors Hot flushes, sexual dysfunction, myalgias/arthralgias? Cognitive dysfunction) Life threatening (persist as long as Rx Continues) Tamoxifen Thrombosis Endometrial Cancer Aromatase Inhibitors Osteoporosis/Fracture? Cardiovascular

15 Taken Together, These Data Support- Consideration of extended adjuvant endocrine therapy Reduces risk by 1/3-1/2 for most patients There might be a group who could consider stopping Not clear who that is Further studies of determination of late risk Biology of primary tumor (multi-gene expression assays, etc) Real time identification of risk

16 Extended Adjuvant Endocrine Therapy Assuming that extended ET reduces late recurrence by ~ ½, How low is low enough to withhold it? RISK of REC/YEAR % PTS WHO WILL BENEFIT <1% risk/year? <0.5% benefit/year 1%/year? ~0.5% benefit/year 2%/year? ~1% benefit/year Must use judgment (yours, patient s) to decide

17 Conclusions: Extended Adjuvant ET Are there better determinants of late risk than just nodal status, tumor size and grade? Biology of primary tumor (multi-gene expression assays, etc) Identification of dormant disease with recurrence potential: Disseminated or circulating tumor cells (DTC, CTC) Circulating cell free tumor DNA (cftdna) Circulating protein or metabolites?

18 Conclusions: Extended Adjuvant ET Are there better determinants of late risk than just nodal status, tumor size and grade? Biology of primary tumor (multi-gene expression assays, etc) Identification of dormant disease with recurrence potential: Disseminated or circulating tumor cells (DTC, CTC) Circulating cell free tumor DNA (cftdna) Circulating protein or metabolites?

19 ER Positive Breast Cancer: Adjuvant Endocrine Therapy What are the prognostic factors for recurrence after 5 years of adjuvant ET in original Primary Cancer Tissue? Multi-parameter molecular biomarker tests IHC4 (By Dowsett and Cuzick et al) 72 gene Recurrence Score (Mammaprint/modified) 21-gene Recurrence Score (OncotypeDx) 8 gene (Endopredict) PAM50 (ProSIGNA) 11 gene (Breast Cancer Index)

20 Prediction Late-Distant Recurrence IHC4 (as performed by Dowsett and Cuzick) ATAC IHC4 High IHC4 Low ~ 1%/year Sestak, et al., J Natl Cancer Inst 105: , 2013

21 Prediction Late-Distant Recurrence Risk of Recurrence Assay (PAM50) ATAC ROR High ROR Low <1%/year Sestak, et al., J Natl Cancer Inst 105: , 2013

22 Prediction of Late-Distant Recurrence OncotypeDx 21-gene RS ATAC ODX High ODX Low Curves appear to come together; Both Appear ~ 2-3%/year Sestak, et al., J Natl Cancer Inst 105: , 2013

23 Prediction of Late-Distant Recurrence OncotypeDx 21-gene RS NSABP B14 Curves do NOT come Appears together; ~ 0.6%/year Low < 1%/year Wolmark et al JCO 2016

24 ER Positive Breast Cancer In 1 or 2 Retrospective Data Sets, Each of These Assays Extended Adjuvant Endocrine Therapy Has Been Reported to Separate Patients with Low from Are there better High prognostic Risk for factors Late Recurrence in the Primary Cancer than just lymph node, tumor size, and grade for recurrence after 5 years of adjuvant ET? Multi-parameter molecular biomarker tests IHC4 (By Dowsett and Cuzick et al) 72 gene Recurrence Score (Mammaprint/modified) 21-gene Recurrence Score (OncotypeDx) 8 gene (Endopredict) PAM50 (ProSIGNA) HOWEVER: ASCO Tumor Marker Guidelines Panel did not feel that the evidence was of sufficiently high level to recommend that any one of these assays should be used to decide whether to continue or stop extended ET after 5 years Harris, Ismaila, McShane, Andre, Collyar, Gonzalez-Angulo, Hammond, Kuderer, Liu, Mennel, Van Poznak, Bast and Hayes, J Clin Oncol 34: , gene (Breast Cancer Index)

25 Conclusions: Extended Adjuvant ET Are there better determinants of late risk than just nodal status, tumor size and grade? Biology of primary tumor (multi-gene expression assays, etc) Identification of dormant disease with recurrence potential: Disseminated or circulating tumor cells (DTC, CTC) Circulating cell free tumor DNA (cftdna) Circulating protein or metabolites?

26 Risk of Recurrence: Three Scenarios NO DORMANT CELLS No DTC detectable in bone marrow or blood (or elsewhere) OR ONLY detectable TDC/Bulk cells No or very, very low chance of recurrence, ever Stop ET CELLS PRESENT, BUT ESCAPED DORMANCY Can detect DTC or evidence of it AND can determine no longer dormant. Risk of Recurrence within next months Treat like established metastases (at present, palliation is goal) CELLS PRESENT, BUT STILL DORMANT Something detectable, but evidence suggest still dormant Risk of much later (>12-18 mos) recurrence elevated but unknown Continue current ( working ) or switch or add something that could be effective but still low toxicity

27 Risk of Late Recurrence: Possible Mechanisms of Escape from Dormancy Cancer Cell Genetics (further mutations) Phenotypes (changes in growth factor receptors, other?) Micro-Environment Oxygen state, vascularization Inflammation Host Immune changes Stress Obesity Other?

28 Risk of Late Recurrence Prognostic factors present at time of decision Disseminated tumor cells/bone marrow Circulating markers ( Liquid Biopsies ) Protein Cell free plasma tumor DNA Circulating tumor cells

29 Risk of Late Recurrence Prognostic factors present at time of decision Disseminated tumor cells/bone marrow Circulating markers ( Liquid Biopsies ) Protein Cell free plasma tumor DNA Circulating tumor cells Sparano, et al. Circulating Tumor Cells and Late Recurrence of Breast Cancer; SABCS 2017

30 40 th Annual San Antonio Breast Cancer Symposium, December 5-9, 2017 Circulating Tumor Cells and Late Recurrence of Breast Cancer Joseph A. Sparano, MD 1, Anne O Neill, MS 2, Katherine Alpaugh, PhD 3, Antonio C. Wolff, MD 4, Donald W. Northfelt, MD 5, Chau T. Dang, MD 6, George W. Sledge, MD 7, Kathy Miller, MD 8 1. Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY; 2. Dana Farber Cancer Institute, Boston, MA; 3. Fox Chase Cancer Center, Philadelphia, PA; 4. Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD; 5. Mayo Clinic, Scottsdale, AZ; 6.Memorial Sloan Kettering Cancer Center, New York, NY; 7. Stanford Cancer Center, Palo Alto, CA; 8. Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN

31 San Antonio Breast Cancer Symposium December 5-9, 2017 Methods: Study Design Population: Stage II-III HER2-negative enrolled in E5103 (NCT ) Treatment: AC-weekly paclitaxel ± bevacizumab + endocrine therapy if ER+ Selection: Recurrence-free years after diagnosis & informed consent CTC Assay: Whole blood (7.5 ml) drawn into fixative-containing tube for CTC identification and enumeration using the CellSearch system at entry Assay results: not reported to clinicians or patients due to uncertainty regarding prognostic information Sparano et al SABCS 2017 This presentation is the intellectual property of the presenter. Contact jsparano@montefiore.org for permission to reproduce and/or distribute. 31

32 San Antonio Breast Cancer Symposium December 5-9, 2017 Results: Time to Recurrence in HR+ Disease (N=353) Median time to recurrence in CTC+: 1.6 years (range years) Recurrence rates per personyear CTC-Pos: 24.7% CTC-Neg: 1.5% 2-Year Recurrence Positive Predictive Value = 35% Negative Predictive Value = 98% Hazard ratio 21.7 (95% C.I ) p <0.001 log rank test Multivariate Cox model Hazard ratio 18.1 (95% C.I ) Sparano et al SABCS 2017 This presentation is the intellectual property of the presenter. Contact jsparano@montefiore.org for permission to reproduce and/or distribute. 32

33 Risk of Late Recurrence Prognostic factors present at time of decision NONE OF THESE HAS BEEN CLINICALLY Disseminated tumor cells/bone marrow VALIDATED AND SHOULD NOT BE Circulating markers ( Liquid Biopsies ) MONITORED OR USED TO MAKE THE Protein Cell free plasma tumor DNA DECISION REGARDING EXTENDED ET!! Circulating tumor cells

34 Late Recurrence: Conclusions Persistent in ER positive early stage disease X yrs Rate reduced by extended ET, but at a cost Concerns: Treating patients with very good prognosis Over-Dx (i.e. assuming that if we find something, it must be true) If Rx does not decrease breast cancer recurrence, it could lead to increased mortality Tamoxifen: AIs: Thrombosis, endometrial CA Fractures,? CVD Research Question: Can we identify- Very favorable prognosis who can stop therapy Poor prognosis who need to Continue Change Add

35 Acknowledgements EBCTCG colleagues and the many research contributors UM and other lab and clinical colleagues Of course, the many thousands of patients who have entered clinical trials to improve the care of those who came after them.

36 Fluorescent in situ Hybridization (FISH) (Not ASCO/CAP Guideline Panel)