Health Disparities Advances in Breast Cancer Treatment Jo Anne Zujewski April 27, 2009
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Breast Cancer Incidence 1994-2003
Breast Cancer Mortality 1994-2003
Access to Care Comorbidity Biology
Access to Care NSABP and CALGB Experience NSABP node neg trials B-13 ER neg 5 yr OS 85% white 83% black B-14 ER pos 5 yr OS 92% white 93% black Blacks-larger, younger, more ER neg, more mastectomies Dignam JJ CA Cancer J Clin 2000:50-64 CALGB 9342 Metastatic breast cancer (paclitaxel) Overall survival Black 10.1 mo White 13.1 mo (p=.0005) Triple negative 44 of 136 patients Decreased OS (8.7 versus 12.9 months) p=0.008 More triple neg in AA women DFS and OS in triple neg did not vary by race Harris JN, et al. Breast Cancer Research 2006
Comorbidity Henry Ford Health System Tumor Registry N=924 1985-1990 Tammemagi CM et al. JAMA 2005
Comorbidity and Race 40% 30% 20% 10% 40% 30% 20% 10% # Comorbidities More comorbidity, worse (all cause, competing cause) survival among blacks Worse breast cancer relapse NOT associated with comorbidity
Seminal observations that have led to the current understanding of breast as a family of related diseases, not a single monolithic process. Hormone Refractory Triple Negative Secondary Resistance HER-2 positive Hormone positive Sorlie T et al, PNAS 2001
Sorlie T et al, PNAS 2001 Subtypes and Prognosis
Triple negative and survival 482 patients with all 3 markers in database Median follow-up 7.9 years Triple neg DDFS 67% DDFS HR 1.79 (1.31-3.53) Disease specific survival 1.79 (1.03-3.22) No difference in local control (83% versus 83%) Others 82% Haffty, BG, et al J Clin Oncol 24:5652-5657.
California Cancer Registry 51,074 with all 3 typed 1999-2003 44,704 other breast 6370 triple neg 12.5 % of total Less than 40 yo 1.53 Black 1.77 Hispanic 1.23 Triple neg relative survival 77% 5 year DFS vs 93% other breast cancers Late stage triple neg survival Non Hispanic black 14% alive 5 years vs 49% other breast cancer in non-hispanic black Non-Hispanic white 36% alive Hispanic 37% Bauer KR, et al Cancer 109:1721-8, 2007
Breast Cancer Subtypes in the Carolina Breast Cancer Study (CBCS) Courtesy of R. Millikan Population-based case-control study of breast cancer risk Phase I 1993-96 40% African-American, 50% less than 50y.o. Immunohistochemistry surrogates for breast cancer subtypes 496 of 851 cases with complete IHC and clinical data
Participant Characteristics Age 50 Premenopausal 53% African-American 40% Stage I II III IV 39% 51% 8% 3% ER-positive 60% HER2-positive 22% High grade 46%
Basal-like Clinical Characteristics AA Premenopausal Postmenopausal White Premenop. Postmenopausal Stage I II III IV Lymph node + Invasive ductal Invasive lobular Mixed Poor histologies Grade III Basal like (n=100) 39% 14% 16% 16% 24% 62% 13% 41% 84% 0 6% 10% 84% HER2+/ER (n=33) 9% 7% 6% 6% 28% 53% 19% 56% 94% 0 6% 0 75% Luminal A (n=255) 36% 59% 51% 58% 44% 47% 9% 34% 70% 12% 9% 3% 31% Luminal B (n=77) 9% 16% 18% 16% 39% 54% 6% 47% 79% 7% 12% 1% 31% P value <0.001 0.06 0.04 <0.001 < 0.001 P53 mutated 44% 43% 15% 23% < 0.001 Carey LA et al, JAMA 2006
Carey LA et al, JAMA Breast Cancer Subtypes, Race and Age N Basallike HER2+ (ER-) Lumina l A Lumina l B Unclass Premenopausal African-American Postmenopausal African-American 97 39% 9% 36% 9% 6% 99 14% 7% 59% 16% 4% Premenopausal non African- American Postmenopausal non African- American 16 4 13 6 TOTAL 49 6 16% 6% 51% 18% 10% 16% 6% 58% 16% 4% 20% 7% 51% 16% 6% P=0.0001
Metastatic potential of triple negative Predominance of visceral and CNS mets Distinct mechanism of metastatic spread Cell lines from Caucasians and AA Examine 14 metastasis genes In vitro differences Atp1b1, CARD 10, KLF 4< Spint 2, ACLY Of 26 human MMP, AA have elevated expression in 12 of these compared with Caucasion Yancy HF, J Carcinogenesis 2007, 6:8
Therapeutic options for triple neg? DNA damage/metabolism cell cycle, proliferation cytoskeletal structural component Optimize cytotoxics Platinum and DNA strand breaks PARP inhibitors Abundant MAP kinases EGFR, c-kit, PI3K, mtor, ras Cleator, S et al oncology.the lancet., 2007 C
Triple Negative Breast Cancer Responds to Conventional Chemotherapy Pathologic Complete Response: T-FAC (N=82)* AC-T (n=107)* Luminal A/B 7% 7% Normal-like 0 NA HER2+/ER- 45% 36% Basal-like/triple negative 45% 26% Rouzier, Clin CancRes 05; Carey, Clin Canc Res 07 Basal like / triple negative breast cancer responds to primary chemotherapy.? Explanation of higher response but worse outcome?
Triple Negative Prognosis Is Particularly Dependent Upon Responsiveness pcr do well, regardless of subtype Non pcr do not do well, especially if triple negative Liedtke, C. et al. J Clin Oncol; 26:1275 1281 2008
CALGB 40603: Triple Negative Neoadjuvant Trial Carboplatin N=400 ER/PR/HER2- Stage II-IIIB Paclitaxel No carboplatin Carboplatin Dose-dense AC S U R G E R Y RT prn Paclitaxel No carboplatin Bevacizumab Breast imaging Blood MUGA Tumor Biopsy Breast imaging Blood (Sikov, PI) Breast imaging Blood MUGA
Breast Cancer Targets? Self sufficiency in growth signals Evading apoptosis Insensitivity to antigrowth signals Sustained angiogenesis Tissue invasion and metastasis Limitless replicative potential Adapted from Hanahan and Weinberg. Cell. 2000;100:57.
1993 NIH Revitalization Act Inclusion of: Women and minorities and their subpopulations in all clinical research Minorities in phase III trials so that valid analysis of differences in intervention effects can be performed Cost is not an acceptable reason for exclusion NIH initiate programs and support for outreach to recruit and retention
NCI Clinical Trials Network NCI Cancer Centers (64), other academic centers Community Clinical Oncology Program (47) Minority-Based Clinical Oncology Program (13) Cancer Disparities Research Partnership Program (5) NCI Community Cancer Centers Program (16)
Minority Enrollment to NCI (CTEP, DCP, RRP) Clinical Trials 50,000 46,948 45,000 40,000 35,000 30,000 32,552 83% 36,412 82% 82% 38,608 81% 40,260 80% 35,314 81% 36,557 81% 32,304 32984 78% 76% 25,000 20,000 15,000 10,000 5,000 0 5,494 6,722 14% 1084 15% 1028 8,892 8,372 9,179 16% 17% 18% 7,400 7,442 7,547 17% 16% 18% 1144 930 1015 1026 1206 1375 8986 FY2000 FY2001 FY2002 FY2003 FY2004 FY2005 FY2006 FY2007 FY2008 21% 1612 Majority Minority Unknown or Not Reported
Minority Enrollment on NCI (CTEP, DCP, RRP) Clinical Trials by Race 5,000 4,500 4721 4513 4501 4,000 3,500 3,000 2,500 2,000 2851 3281 1,500 1,000 500 0 871 948 886 1,024 575 125 255 2 83 180 121 235 3 16 110 222 54 115 72 152 FY2000 FY2001 FY2002 FY2003 FY2004 American Indian or Alaska Asian Black or African American Native Hawaiian or Other PacificIslander More than one race
Minority Enrollment on NCI (CTEP, DCP, RRP) Clinical Trials by Race 4,500 4,000 3,500 3567 3355 3340 3955 3,000 2,500 2,000 1,500 1,000 1,022 1,061 1,090 1209 500 0 199 52 102 207 73 106 233 59 94 209 51 106 FY2005 FY2006 FY2007 FY2008 American Indian or Alaska Asian Black or African American More than one race Native Hawaiian or Other PacificIslander
13 Minority based CCOPs Minority-Based CCOPS Grant/Fiscal Year # of Funded MBCCOPS Treatment Accrual Prevention & Control Accrual Overall Accrual # of Minority Patients % Minority Overall 2000 8 425 358 783 446 57 % 2001 10 642 541 1183 676 57 % 2002 11 567 682 1249 901 72 % 2003 11 521 930 1451 1088 75 % 2004 13 673 467 1140 674 59 % 2005 13 709 428 1137 579 51 % 2006 13 684 393 1077 602 56% 2007 14 805 776 1581 965 61% Total (2000 2007) 5,026 4,575 9,601 5,931 Community Clinical Oncology Program (CCOPS) 2000 51 6241 4872 11,113 938 8 % 2001 50 6328 7936 14,264 991 7 % 2002 50 5257 6373 11,630 888 8 % 2003 50 5269 6963 12,232 1,038 8 % 2004 50 6729 4871 11,600 1,095 9 % 2005 50 7239 4783 12,022 846 7 % 2006 50 5718 4601 10,319 974 9 % 2007 49 5533 6020 11,553 1,115 10% Total (2000 2007) 48,314 46,419 94,733 7,885
NCI Community Cancer Centers Program: Clinical Trials Goals: Increase Accrual to all trials Accrual focus: Minorities and Underserved Multimodality and early phase trials 10 Organizations selected
Center for Health Disparities & Other Partners Patient Navigator Program Partnership (MBCCOP, CCOPs, NCCCP, Cancer Centers) Community Network Program Education and collaboration with clinical trials network Baquet, et al., Analysis of Maryland Cancer Patient Participation in National Cancer Institute Supported Cancer Treatment Clinical Trials, JCO, 2008 ENACCT (Ed. Network to Advance Ca Clinical Trials
Trans-NCI Clinical Trials Accrual Working Group (CTAWG) Goals Foster collaboration and information sharing of clinical trials accrual initiatives among the NCI Centers, Offices, Divisions and Programs that review, support, and fund clinical trials. Develop initiatives that promote successful clinical trial accrual practices
CTAWG Goals (cont.) CTAWG is exploring holding an interactive workshop in 2010 on clinical trial accrual strategies CTAWG with OCE is investigating how sites might use an interactive web site of evidencedbased accrual strategies.
New! NCI Promotional materials to assist in recruitment