Geriatric Oncology Breast Cancer

Transcription

1 Geriatric Oncology Breast Cancer A 78 year old college-educated woman, never married Moderate hypertension, controlled type 2 diabetes active, PS.0 Diagnosis: non-tender 4 cm mass, movable, on the upper outer quadrant of her left breast and no palpable axilary lymph nodes. Treatment: Lumpectomy with sentinel node biopsy

2 Geriatric Oncology Breast Cancer Pathology: Invasive ductal carcinoma with a 5.0cm lesion, hystologic grade 3, with lymphovascular invasion. Surgical margins were negative. Sentinel node biopsy was positive for micrometastasis, no further dissection was done. Immunohistochemical staining: positive for estrogen and progesterone receptors, Luminal B subtype Ki-67 25% HER-3+ STAGE IIB (T1N1micM0).

3 Questions to be discussed Optimal adjuvant treatment? Do we change Radiation indications? Anthracycline use, is it possible? Trastuzumab with RXT, safe?

4 I Congresso de Oncologia D Or 5 e 6 de julho de 2013 Questoes na Adjuvância em Pacientes Acima dos 70 Anos Câncer de Mama Antonio C. Wolff, MD, FACP, FASCO Professor de Oncologia Programa de Câncer de Mama Johns Hopkins University School of Medicine This presentation is the intellectual property of the presenter; please contact him for permission to reprint and/or distribute

5 How Do Clinicians Make Decisions About Adjuvant Therapy? Before & After Oxford Overview Chemo decisions based on anatomy: Nodal status Tumor size (add endocrine Rx if ER+) Since 2005 Post Overview? Greater focus on biologic subtype: ER+/HER2-, HER2+, or Triple negative Don t forget the host!

6 5y of TAM on Outcome at 15 years EBCTCG, Lancet 2011

7 TAM Effects According to Age Annual Hazards for Events Age Recurrence CBC Uterine Cancer < EBCTCG, Lancet 2011

8 EBCTCG 2010 Data in for all RCTs started between of: 1. Taxane vs non-taxane (33 trials, ) 2. Any A vs std/near std CMF (20 trials, ) 3. Higher vs lower dose A (6 trials, ) 4. Polychemo vs no chemo (64 trials, ) Lancet 379:432, 2012

9 EBCTCG 2010 Data in for all RCTs started between of: 1. Taxane vs non-taxane (33 trials, ) 2. Any A vs std/near std CMF (20 trials, ) 3. Higher vs lower dose A (6 trials, ) 4. Polychemo vs no chemo (64 trials, ) Lancet 379:432, 2012

10 EBCTCG 2010 Data in for all randomized clinical trials started between of: 1. Taxane vs nontaxane (33 trials, ) 2. Any A vs standard/near standard CMF (20 trials, ) 3. Higher vs lower dose A (6 trials, ) 4. Polychemo vs no chemo (64 trials, ) Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Lancet. 2012;379(9814):

11 Oxford Overview 2010 Main Findings per the Authors In all meta-analyses involving taxane or anthracycline regimens, proportional reductions in early recurrence, any recurrence, and breast cancer mortality were largely independent of age, nodal status, size, differentiation (high or intermediate; relatively few low grade), or ER status (ER-poor or ER+) Even in strongly ER+, chemo did at least somewhat affect outcome, although not necessarily to exactly the same extent as in less strongly ER+ EBCTCG. Lancet. 2012;379(9814):

12 St Gallen Consensus Panel 2009 What St Gallen Said It was recognized that clinical trials are very useful for identifying effective treatments, but fall short of defining the optimal treatment for individual patients St Gallen Consensus Panel 2009 Goldhirsch A, et al..ann Oncol. 2009;20(8):

13 Time-Dependent Effects of Adjuvant Rx SEER Data on long term follow-up may not have been long enough for ER+ disease Jatoi I et al, J Clin Oncol 2011;29:1

14 NSABP B-13 Local Rx ± Adjuvant Chemo in ER-neg After 14y of observation (no chemo) of patients with stage 1 ER-neg breast cancer: ~ 49% disease-free ~ 69% alive Fisher, JNCI Monograph 30:62, 2001

15 CALGB Stratification Age 65-69,70-80,80+; PS 0-1 vs 2;HER2 +/-/unk Randomize CMF 6 cycles or AC 4 cycles CMF; Cyc 100 day 1-14, MTX 40 and FU 600 d1,8 Q4w AC; Dox 60, Cyc 600 d1 Q3w Capecitabine (X) for 6 cycles 2000 d1-14 Q3w All doses per M CALGB 49907

16 Receptor-Positive Tumors Receptor-Positive Tumors Relapse-Free Survival By Arm Overall Survival By Arm Receptor-Negative Tumors Relapse-Free Survival By Arm Proportion Relapse-Free Proportion Relapse-Free Proportion Surviving Years From Study Entry Years From Study Entry CMF/AC Capecitabine N= 218 N= 209 Events= 21 Events= 26 Unplanned Subset Analysis CMF/AC Capecitabine N= 218 N= 209 Receptor-Negative Tumors Overall Survival By Arm Events= 15 Events= Proportion Surviving Years From Study Entry Years From Study Entry CMF/AC Capecitabine N= 106 N= 97 Events= 14 Events= 34 CMF/AC Capecitabine N= 106 N= 97 Events= 9 Events= CALGB 49907

17 Trials of One Year of Trastuzumab Trial Strategy DFS HR B-31/ N9831 HERA BCIRG 006 N9831 PACS04 AC-Pac ± concurrent H Chemo ± sequential H AC-Doc ± concurrent H AC-Doc vs TCH AC-Pac ± sequential H FEC or ED ± sequential H 0.48 (2005) 0.64 (2007) 0.64 (2011) 0.75 (2011) 0.87 (2005) 0.96 (2009) X-over to trastuz. 20.9% 52% 1.6% - DFS HR OS HR Reference 0.52 (2011) 0.76 (2011) (2011) 0.61 (2011) 0.85 NS (2011) 0.63 (2011) (2011) 5y DFS 80.1% (vs 84.4% concomitant) Romond 2005, Perez 2011 Smith 2007, Gianni 2011 Slamon 2011 Perez 2005 (abstract), Perez NS Spielmann 2009

18 SABCS, UTHSC Abstract S3-5 Dec 6, 2012 Myelodysplatic Syndrome and/or Acute Myelogenous Leukemia (MDS and/or AML) After a Breast Cancer Diagnosis: the NCCN Experience Judith E. Karp 1, Amanda Blackford 1, Kala Visvanathan 1, Hope S. Rugo 2, Beverly Moy 3, Lori J. Goldstein 4, Keith Stockerl-Goldstein 5, Leigh Neumayer 6, Terry S. Langbaum 1, Melissa E. Hughes 7, Jane C. Weeks 7, and Antonio C. Wolff 1 1 Johns Hopkins Kimmel Cancer Center; 2 University of California San Francisco; 3 Massachusetts General Hospital; 4 Fox Chase Cancer Center; 5 Washington University School of Medicine; 6 University of Utah School of Medicine; and 7 Dana Farber Cancer Institute This presentation is the intellectual property of the presenter; please contact awolff@jhmi.edu for permission to reprint and/or distribute

19 Treatment of Breast Cancer A Balance Between Benefits and Harms Adjuvant therapy has been key to the observed outcome improvements (DFS/OS) in breast cancer Key to remember that improvements in overall survival already take into account any mortality from possible therapy-related toxicities However, these complications may still negatively impact on health-related measures among cancer survivors Therefore, it is important to: o measure their prevalence among breast cancer survivors o identify factors that could discriminate between those likely to benefit and those likely to be harmed by various interventions

20 Effects After Breast Cancer Therapy Early reports of leukemia o After chemo or radiation (eg, Fisher B, JCO 3:1640, 1985) Contemporary therapies o NSABP trials (Smith R, JCO 21:1195, 2003) 0.27% risk of MDS/AML after 8y Greater risk if RT after lumpectomy CSFs use may be independent correlated with higher risk o NSABP B38 (Swain, ASCO LBA 1000, 2012) 0.49% risk of 5.3y (all 3 arms used CSFs) o Oxford Overview thus far only briefly reported on leukemia risk (EBCTCG, Lancet 379:432, 2012) More details in the upcoming Cycle

21 Acute Myelogenous Leukemia An Environmental/Occupational Cancer Etiologic Factors in Adults % AML Genetic Abnormalities Environmental/Occupational Exposure Benzene, petroleum, organic solvents, arsenical pesticides, radiation Therapeutic Agents Topoisomerase-targeting agents (eg, anthracyclines*) DNA-damaging alkylating agents (eg, cyclophosphamide**) Microtubule inhibitors ~ 30-35% ~ 15-20% None at present -5/5q, -7/7q, 3q26 T(8;21), +8, +21 Translocations (MLL 11q23) -5/5q, -7/7q, 3q26 AML-1 mutation (21q22) -

22 Acute Myelogenous Leukemia An Environmental/Occupational Cancer Etiologic Factors in Adults % AML Genetic Abnormalities Environmental/Occupational Exposure Benzene, petroleum, organic solvents, arsenical pesticides, radiation Therapeutic Agents Topoisomerase-targeting agents (eg, anthracyclines*) DNA-damaging alkylating agents (eg, cyclophosphamide**) Microtubule inhibitors ~ 30-35% ~ 15-20% None at present -5/5q, -7/7q, 3q26 T(8;21), +8, +21 Translocations (MLL 11q23) -5/5q, -7/7q, 3q26 AML-1 mutation (21q22) - Therapeutic Agents Latency Onset Phenotype *Anthracyclines 1 3 years (range ) No prodrome M4, M5 common (M3 with mitoxantrone) **Cyclophosphamide 4 6 years (range 1 20) Preceded by MDS M6, M7

23 Leukemia Demographics New Cases and Deaths for 2012 AML Incidence Rate per 100,000 Population MDS New Cases 13,780 (plus 6,230 leukemia NOS ) 18,169 Deaths 10,200 (plus 6,660 leukemia NOS ) SEER only recently began Total 23,980 (plus 12,890 leukemia NOS ) to maintain stats for MDS; 2011 data not reported Age Groups AML Age Groups MDS < Overall 4.4 Overall 12.5 Sources: SEER ; Leukemia & Lymphoma Society, Facts 2012

24 Study Design (I of III) Patient Cohort Stage I-III patients first seen Jul 1997-Dec sites that joined database effort before 2000 Terms used to identify blood neoplasms included: o ICD9 Codes Leukemia unspecified 208, 208.0, and MDS 238.7, AML 205, lymphoid leukemia 204, monocytic leukemia 206, other 207 o Drug terms l-asparaginase, decitabine, 5-azacytidine

25 Patient Flow Diagram Breast Cancer Diagnosis at NCCN n = 22,248 excluded Incident (first dx) breast cancer n = 20,533, median follow-up 5.1 years Prior history of cancer n = 1,715.CLL before BC, n = 1.Ovarian cancer before AML and BC, n = 1.Uterine cancer before AML and BC, n = 1

26 Patient Flow Diagram Breast Cancer Diagnosis at NCCN n = 22,248 excluded Incident (first dx) breast cancer n = 20,533, median follow-up 5.1 years Prior history of cancer n = 1,715.CLL before BC, n = 1.Ovarian cancer before AML and BC, n = 1.Uterine cancer before AML and BC, n = 1 Patients without leukemia, n = 20,482 Censored at date of last NCCN contact n = 16,092 Censored at first date of other cancer event n = 3,935 Died while being followed at NCCN n = 455 Patients w/ leukemia n = 51 (0.25%).Locoregional breast cancer recurrence before AML, n = 1.2 nd breast cancer diagnosis before AML, n = 1

27 Patient Characteristics Cohorts Breast Cancer Only n = 20,482 Leukemia after Breast Cancer n = 51 p- value Age Median (range) 53.9 years (range, ) 60.2 years (range, ) 0.02 < age 50 38% (7,745) 22% (11) age 50 62% (12,737) 78% (40) 0.02 Race White 87% (17,921) 92% (47) African American 8% (1,600) 6% (3) 0.72 Other 5% (961) 2% (1)

28 Local and Systemic Therapy Cohorts A and/or C Chemotherapy Breast Cancer Only n = 20,012* Leukemia after Breast Cancer n = 51 None or just endocrine Rx 38% (7,569) 27% (14) 4 cycles 51% (10,268) 61% (31) 6 cycles 11% (2,175) 12% (6) Local & Systemic Rx None 13% (2,548) 4% (2) Radiation, but no Chemo 25% (5,021) 24% (12) Chemo, but no Radiation 16% (3,218) 18% (9) Chemo and Radiation 46% (9,225) 55% (28) p-value *Analyses of patterns of care excluded 470 patients who did not have at least 6 months of appropriate follow-up at an NCCN site.

29 Leukemia Cohort i. No Leukemia n = 20,482 Leukemia n = 51 ii. Myeloid Leukemia n = 44 Lymphoid Leukemia n = 7 iii. AML n = 25 MDS/AML n = 15 CML n = 3 MPD n = 1 ALL n = 3 CLL n = 4 iv. Acute Monocytic Leukemia (M4/M5) n = 11 Chronic Myelomonocytic Leukemia n = 1

30 Hazard Ratios for Risk of Leukemia Hazard Ratio (95% CI) (0.6, 12.47) 5.68 (1.11, 29.04) 5.64 (1.2, 26.46) p values

31 Rates of Leukemia per 1,000 Patient-Year

32 Cumulative Incidence of Leukemia Groups n P-Y Events 5-Year Incidence 10-year Incidence All 20, , (0.17, 0.33) 0.46 (0.31, 0.61) Surgery 2,550 12, (-0.04, 0.14) 0.2 (-0.11, 0.51) Radiation 5,033 28, (0.06, 0.33) 0.44 (0.15, 0.74) Chemo 3,227 17, (0.07, 0.53) 0.52 (0.13, 0.91) Chemo/RT 9,253 52, (0.19, 0.46) 0.51 (0.29, 0.74)

33 Cumulative Incidence Across Datasets NSABP ACx4 Sub-Group Smith R, JCO 21:1195, 2003 Chemo Sub-Group NCCN Database n 4,483 12,480 Age 50 (average) 53 (median) Censored at First Event? If not If censored Yes Leukemia Events Patient-Years 34,400 29,193 69,293 Rate/1,000 P-Y 0.32? 0.54 Cumulative Incidence 8y 8y 5y 10y

34 Risk of Marrow Neoplasm Adjuvant chemotherapy was associated with a cumulative 10-year incidence of leukemia of ~ 0.5% that appears to be higher than previously reported Almost half of the events occurred beyond year 5 Radiation alone appears to be a risk factor, but may not add much to patients already treated with chemotherapy Leukemia risk was not limited to MDS/AML, and cases of high risk lymphoid leukemia were observed This study highlights the challenges of studying infrequent but important clinical events Most important, longitudinal databases like NCCN are critically needed

35 Case #2 61 year old healthy female Screening mammogram showed abnormal calcifications in upper outer quadrant (UOQ) right breast Clinical exam confirms palpable 2.0 cm mass in right UOQ with negative axilla (ct1n0) Ultrasound showed 1.4 cm irregular hypoechoic nodule and no suspicious axillary lymph nodes (LNs)

36 Case #2 Core biopsy Infiltrative ductal carcinoma (IDC), grade 1. Immunohistochemistry (IHC) markers showed ER/PR 100% strong positive, HER2 0, and Ki67 5% Labs Normal blood cell count, liver enzymes, and alkaline phosphatase

37 Case #2 Patient underwent lumpectomy and sentinel lymph node biopsy (SLNBx) Pathology Grade 1 IDCa, 1.4 cm, without lymphovascular invasion, IHC markers not repeated SLNBx showed 1 of 3 SLNs with a 0.4 cm focus of macrometastasis pt1cn1a - stage 2a Further axillary surgery not performed

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40 Age 61 Age 71 Age 81

41 Adjuvant Treatment in Older Adults Who should receive chemo? Who should receive radiation? Always give endocrine therapy? What are the preferred chemo schedules? Should we use geriatric scores? Which ones? Long term follow-up, same or different?

42 I Congresso de Oncologia D Or 5 e 6 de julho de 2013 Questoes na Adjuvância em Pacientes Acima dos 70 Anos Câncer de Mama Antonio C. Wolff, MD, FACP, FASCO Professor de Oncologia Programa de Câncer de Mama Johns Hopkins University School of Medicine This presentation is the intellectual property of the presenter; please contact him for permission to reprint and/or distribute