Health Disparities Advances in Breast Cancer Treatment. Jo Anne Zujewski April 27, 2009

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1 Health Disparities Advances in Breast Cancer Treatment Jo Anne Zujewski April 27, 2009

2 Disclaimer

3 Breast Cancer Incidence

4 Breast Cancer Mortality

5 Access to Care Comorbidity Biology

6 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

7 Comorbidity Henry Ford Health System Tumor Registry N= Tammemagi CM et al. JAMA 2005

8 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

9 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

10 Sorlie T et al, PNAS 2001 Subtypes and Prognosis

11 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 ( ) Disease specific survival 1.79 ( ) No difference in local control (83% versus 83%) Others 82% Haffty, BG, et al J Clin Oncol 24:

12 California Cancer Registry 51,074 with all 3 typed ,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

13 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 % African-American, 50% less than 50y.o. Immunohistochemistry surrogates for breast cancer subtypes 496 of 851 cases with complete IHC and clinical data

14 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%

15 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 < P53 mutated 44% 43% 15% 23% < Carey LA et al, JAMA 2006

16 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 TOTAL % 6% 51% 18% 10% 16% 6% 58% 16% 4% 20% 7% 51% 16% 6% P=0.0001

17 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

18 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

19 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?

20 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:

21 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

22 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.

23 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

24 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)

25 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, % 76% 25,000 20,000 15,000 10,000 5, ,494 6,722 14% % ,892 8,372 9,179 16% 17% 18% 7,400 7,442 7,547 17% 16% 18% FY2000 FY2001 FY2002 FY2003 FY2004 FY2005 FY2006 FY2007 FY % 1612 Majority Minority Unknown or Not Reported

26 Minority Enrollment on NCI (CTEP, DCP, RRP) Clinical Trials by Race 5,000 4, ,000 3,500 3,000 2,500 2, ,500 1, , FY2000 FY2001 FY2002 FY2003 FY2004 American Indian or Alaska Asian Black or African American Native Hawaiian or Other PacificIslander More than one race

27 Minority Enrollment on NCI (CTEP, DCP, RRP) Clinical Trials by Race 4,500 4,000 3, ,000 2,500 2,000 1,500 1,000 1,022 1,061 1, FY2005 FY2006 FY2007 FY2008 American Indian or Alaska Asian Black or African American More than one race Native Hawaiian or Other PacificIslander

28 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 % % % % % % % % Total ( ) 5,026 4,575 9,601 5,931 Community Clinical Oncology Program (CCOPS) , % , % , % ,232 1,038 8 % ,600 1,095 9 % , % , % ,553 1,115 10% Total ( ) 48,314 46,419 94,733 7,885

29 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

30 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

31 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

32 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.

33 New! NCI Promotional materials to assist in recruitment