Shubhada Dhage

A genomic ruler to assess oncogenic transition between breast tumor and stroma

Background Cancers induce gene expression alterations in stroma surrounding tumors that supports cancer progression. However, it is actually not at all known the extent of altered stromal gene expression enacted by tumors nor the extent to which altered stromal gene expression penetrates the stromal tissue. Presently, post-surgical “tumor-free” stromal tissue is determined to be cancer-free based on solely on morphological normality—a criteria that has not changed in more than 100 years despite the existence of sophisticated gene expression data to the contrary. We therefore investigated the extent to which breast tumors alter stromal gene expression in three dimensions in women undergoing mastectomy with the intent of providing a genomic determination for development of future risk of recurrence criteria, and to inform the need for adjuvant full-breast irradiation. Methods and findings Genome-wide gene expression changes were determined in histopathologically normal breast tissue in 33 women undergoing mastectomy for stage II and III primary invasive ductal carcinoma at serial distances in three dimensions from the tumor. Gene expression was determined by genome-wide mRNA analysis and subjected to metagene mRNA characterization. Tumor-like gene expression signatures in stroma were identified that surprisingly transitioned to a plastic, normalizing homeostatic signature with distance from tumor. Stroma closest to tumor displayed a pronounced tumor-like signature enriched in cancer-promoting pathways involved in disruption of basement membrane, cell migration and invasion, WNT signaling and angiogenesis. By 2 cm from tumor in all dimensions, stromal tissues were in transition, displaying homeostatic and tumor suppressing gene activity, while also expressing cancer supporting pathways. Conclusions The dynamics of gene expression in the post-tumor breast stroma likely co-determines disease outcome: reversion to normality or transition to transformation in morphologically normal tissue. Our stromal genomic signature may be important for personalizing surgical and adjuvant therapeutic decisions and risk of recurrence.

Abstract B49: Factors affecting the treatment of young women with breast cancer at tertiary referral public and private hospitals

Background: Disparities persist in receipt of treatment and outcomes of breast cancer patients with varying race, English proficiency, and socioeconomic backgrounds. This is confounded in young women (≤ 45 years old), as age becomes an additional factor. We sought to assess our surgical experience with young breast cancer patients, at a public safety-net hospital (BH) and a private cancer center (PCC) that are staffed by specialty trained providers from the same university. Methods: We reviewed demographic and clinical-pathologic data from 275 breast cancer patients with invasive breast cancer (Stage I-III) 45 years old and younger from the public and private hospital IRB-approved databases. There were 69 patients in the BH group and 206 patients in the PCC group. Demographic variables (race, education, and primary language), surgery type, method of presentation, and stage were analyzed using Pearson9s chi-square tests and binary logistics. Results: At PC the patients were Caucasian (68%), Asian (11%), Hispanic (10%), and African American (8.7%). At BH patients were Spanish/Hispanic/Latino (47.8%), Asian (27.5%), and African American (10.1%). The majority of patients (82%) at PC had a college or graduate degree compared to 18.6% of the patients at BH (P Conclusion: Young women with breast cancer treated at public hospital affiliated with an academic center had equivalent surgical treatment regardless of race, primary language, method or stage or presentation, and education level as young breast cancer patients treated at an academic private hospital. Citation Format: Ami Patel, Shubhada Dhage. Factors affecting the treatment of young women with breast cancer at tertiary referral public and private hospitals [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr B49.

What matters most: protocol for a randomized controlled trial of breast cancer surgery encounter decision aids across socioeconomic strata

BackgroundBreast cancer is the most commonly diagnosed malignancy in women. Mastectomy and breast-conserving surgery (BCS) have equivalent survival for early stage breast cancer. However, each surgery has different benefits and harms that women may value differently. Women of lower socioeconomic status (SES) diagnosed with early stage breast cancer are more likely to experience poorer doctor-patient communication, lower satisfaction with surgery and decision-making, and higher decision regret compared to women of higher SES. They often play a more passive role in decision-making and are less likely to undergo BCS. Our aim is to understand how best to support women of lower SES in making decisions about early stage breast cancer treatments and to reduce disparities in decision quality across socioeconomic strata.MethodsWe will conduct a three-arm, multi-site randomized controlled superiority trial with stratification by SES and clinician-level randomization. At four large cancer centers in the United States, 1100 patients (half higher SES and half lower SES) will be randomized to: (1) Option Grid, (2) Picture Option Grid, or (3) usual care. Interviews, field-notes, and observations will be used to explore strategies that promote the interventions’ sustained use and dissemination. Community-Based Participatory Research will be used throughout. We will include women aged at least 18 years of age with a confirmed diagnosis of early stage breast cancer (I to IIIA) from both higher and lower SES, provided they speak English, Spanish, or Mandarin Chinese. Our primary outcome measure is the 16-item validated Decision Quality Instrument. We will use a regression framework, mediation analyses, and multiple informants analysis. Heterogeneity of treatment effects analyses for SES, age, ethnicity, race, literacy, language, and study site will be performed.DiscussionCurrently, women of lower SES are more likely to make treatment decisions based on incomplete or uninformed preferences, potentially leading to poorer decision quality, quality of life, and decision regret. This study hopes to identify solutions that effectively improve patient-centered care across socioeconomic strata and reduce disparities in decision and care quality.Trial registrationNCT03136367 at ClinicalTrials.govProtocol version: Manuscript based on study protocol version 2.2, 7 November 2017.

Primary Large Cell Neuroendocrine Carcinoma of the Breast, a Case Report with an Unusual Clinical Course

Large cell neuroendocrine carcinoma of the breast (NECB) is an extremely rare type of breast cancer; little is known about effective chemotherapies, and data on pathologic response to treatment are unavailable. We report the case of a 34‐years‐old woman with large cell NECB with initial clinical and pathologic evidence of treatment response to anthracycline‐containing neo‐adjuvant therapy. Histologic reassessment early during anthracycline chemotherapy revealed cell death with necrosis of 50% of the tumor cells seen in the biopsy specimen. After completing neo‐adjuvant chemotherapy, the patient underwent breast‐conserving surgery. Pathologic evaluation of the surgical specimen showed a partial response but margins were positive for residual carcinoma. Despite repeated neo‐adjuvant chemotherapy, radiotherapy, and surgical resection, the tumor grew rapidly between surgeries and recurred systemically. Therefore, we review the literature on large cell NECB and its treatment options.

Genetic counseling and testing of an underserved population at a large city hospital.

38 Background: Genetic counseling and testing for hereditary breast and ovarian cancer is underutilized in low-income and racial/ethnic women. We examine the number of patients referred for genetic counseling over from 2011-2012, clinic referral pattern, and number of patients tested in a population of largely underserved, immigrant patient population. METHODS The study was conducted in Bellevue Hospital. A retrospective review of patients referred to this institutions high-risk clinic was analyzed. Demographics, insurance status, BRCA status, if tested, and source of referral were collected. RESULTS Between 2011-2012, 196 patients were referred for genetic counselling. The majority of the referrals came from specialty clinics: Breast Surgery (42%), Medical Oncology (24%) and Gyn (8.7%). 17.5% were classified as other. One percent of consults came from internal medicine, 0.5% from womens clinic, 4% were referred from family members. Of those patients counseled, 83 were tested. Breast surgery had the highest yield with 49% of the patients tested, followed by med onc (33%). One patient refused testing. Forty-seven of our patients were able to receive genetic testing through Myriad hardship, thirty-three through Medicaid, two paid by Bellevue Hospital, and one by private insurance. Five patients were BRCA1 positive, five patients were BRCA2 positive (12% of patients tested); An additional five patients were BRCA2 MUS. Racial/ethnic breakdown of the BRCA positive patients were 40% Asian, 20% Latina, 30% African American, 10% White. Four patients had a personal history of BrCa, two patients personal history of OvCa, one patient personal history of BCa/OvCa, and three patients FHBCa/OvCa. CONCLUSIONS Genetic testing for HBOC can be underutilized in low-income and racial/ethnic women due to lack of insurance and lack of education. It is possible to get many high-risk women tested and most patients are receptive to testing when the benefits of testing are clearly explained. Our results indicate that while cancer specialists are referring high-risk patients, there may be room for education on the part of primary care specialists to refer more unaffected high risk patients. This may afford patients the opportunity to make better informed screening and treatment decisions.

Abstract P5-04-09: Redefining the breast tumor margin through genomics of the tumor-stromal interaction

Objectives: Emerging data suggest that breast tumors enact gene expression changes in the surrounding stroma, facilitating future recurrence, cancer progression/invasion, metastasis, and altering therapeutic response. The extent to which this alteration penetrates the surrounding breast tissue has not been characterized. It is important to understand both the genomics of the tumor and the tissue that remains following surgery. This relationship could ultimately impact treatment decisions for effective surgery and adjuvant therapy based on the biological impact of the tumor on its anatomical surroundings.Methods: 32 patients undergoing mastectomy for invasive cancer from 2009-2012, had 9 tissue samples placed in RNA later: tumor, and stroma every 5 mm to 20 mm in two directions. A pathologist verified that the stroma was devoid of cancer cells. 108 tissues were analyzed for genome-wide mRNA expression by Affymetrix U133A 2+ arrays: 27 tumor, 29 5mm, 21 10mm, 11 15mm, and 20 20mm regions. RNA was purified by RNeasy chromatography (Qiagen) and assayed for integrity and concentration by Agilent Bioanalysis. SVM, ANOVA and PCA were performed to establish gene expression patterns, clustering and FDR in all tumor sets.Results We propose a gene expression profile/ map of the impact of the breast tumor on non-cancer stromal tissue in the breast. SVM analysis showed paired gene significance based on stromal proximity at all distances, which decreased in similarity with radial distance (closer stromal tissue to tumor had fewer differentially expressed genes). Analysis of gene expression patterns, PCA, unsupervised and supervised clustering demonstrate that the 5 mm region are significantly related to tumor gene expression profiles in almost all of the patients.In contrast, stromal tissue at 10mm, 15mm, and 20mm from the tumor-free margin display gene expression profiles that are similar to each other.But, with reduced similarity to tumor and 5mm. In a small number of patients, stroma at 10-15mm also displayed gene expression profiles significantly consistent with a tumor-like signature. Further analysis for the highest ranked 300 transcripts with the lowest FDR scores based on ANOVA are fully shared by the tumor and 5mm regions in over 30% the patients. A genomic signature is emerging that occurs in the stroma in both the tumor like and non-tumor like regions. Conclusion: These results show that breast tissue devoid of tumor cells is genomically highly related to the tumor at the 5mm, and even from regions 10, 15, and 20mm beyond cancer-free margins in some patients,, corresponding to regions considered histologically “normal”. We suggest that in a subset of patients, cancer-free stromal tissue is highly similar to the tumor. This implicates tumor imprinting as a means of genetically altering stromal tissues in a manner that is consistent with a potential for increased recurrence and de novo cancer development. In order to improve the effectiveness of breast cancer therapy, further determination of tumor/stromal interaction (determining optimal disease free tissue based on genomics and tumor promoting tissue), could directly impact both surgical and disease outcomes.Fig 1. Heatmap-Gene Expression in tumor&5mm are similar, but different from 10, 15, 20. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-04-09.

The impact of screening mammography in breast cancer patients age 40-49 at an urban city hospital.

1598 Background: Recent recommendations by the U.S. Preventive Services Task Force were based on population-based studies and meta-analyses that did not specifically address minority women. A recognized disparity in health care delivery is the underutilization of screening services by minority patients. The purpose of this study was to characterize the clinico-pathologic features multi-ethnic breast cancer patients at an urban tertiary hospital who would not be screened under these new guidelines. METHODS A retrospective chart review of breast cancer cases diagnosed between 2005-09 at Bellevue Hospital was performed. Data included age, stage, presentation (palpable vs non-palpable), ethnicity, and mammographic findings. RESULTS Of 520 cases, 110 (21%) were 40-49 yrs old; data were available for 93. The majority were Chinese (n==36), Hispanic (n==31), or African-American (n==21). Only 5 were Caucasian. Fifty-two (56%) presented with palpable masses vs 41 (44%) with non-palpable cancers. The majority had heterogeneously dense tissue on mammography. Patients with non-palpable lesions were more likely to have been detected by screening mammography, more likely to have had a mammogram the prior year (p == <0.001), and were more likely to have had early-stage disease (p == 0.004) than those with palpable masses. CONCLUSIONS Among minority women with breast cancer, we identified a significant percentage (21%) who would not have been screened under the new guidelines due to their age. Furthermore, most women presented with palpable masses and were not being screened regularly as recommended by current guidelines. Targeted interventions should continue to be directed at minority populations to increase participation in screening programs and narrow the disparities in mammography utilization and stage at presentation. [Table: see text].