Browsing by Author "Sledge, George W., Jr."

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    Adjuvant Chemotherapy Guided by a 21-Gene Expression Assay in Breast Cancer
    (Massachusetts Medical Society, 2018-07) Sparano, Joseph A.; Gray, Robert J.; Makower, Della F.; Pritchard, Kathleen I.; Albain, Kathy S.; Hayes, Daniel F.; Geyer, Charles E., Jr.; Dees, Elizabeth C.; Goetz, Matthew P.; Olson, John A., Jr.; Lively, Tracy; Badve, Sunil S.; Saphner, Thomas J.; Wagner, Lynne I.; Whelan, Timothy J.; Ellis, Matthew J.; Paik, Soonmyung; Wood, William C.; Ravdin, Peter M.; Keane, Maccon M.; Gomez Moreno, Henry L.; Reddy, Pavan S.; Goggins, Timothy F.; Mayer, Ingrid A.; Brufsky, Adam M.; Toppmeyer, Deborah L.; Kaklamani, Virginia G.; Berenberg, Jeffery L.; Abrams, Jeffrey; Sledge, George W., Jr.; Pathology and Laboratory Medicine, School of Medicine
    BACKGROUND The recurrence score based on the 21-gene breast cancer assay predicts chemotherapy benefit if it is high and a low risk of recurrence in the absence of chemotherapy if it is low; however, there is uncertainty about the benefit of chemotherapy for most patients, who have a midrange score. METHODS We performed a prospective trial involving 10,273 women with hormone-receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative, axillary node–negative breast cancer. Of the 9719 eligible patients with follow-up information, 6711 (69%) had a midrange recurrence score of 11 to 25 and were randomly assigned to receive either chemoendocrine therapy or endocrine therapy alone. The trial was designed to show noninferiority of endocrine therapy alone for invasive disease–free survival (defined as freedom from invasive disease recurrence, second primary cancer, or death). RESULTS Endocrine therapy was noninferior to chemoendocrine therapy in the analysis of invasive disease–free survival (hazard ratio for invasive disease recurrence, second primary cancer, or death [endocrine vs. chemoendocrine therapy], 1.08; 95% confidence interval, 0.94 to 1.24; P=0.26). At 9 years, the two treatment groups had similar rates of invasive disease–free survival (83.3% in the endocrine-therapy group and 84.3% in the chemoendocrine-therapy group), freedom from disease recurrence at a distant site (94.5% and 95.0%) or at a distant or local–regional site (92.2% and 92.9%), and overall survival (93.9% and 93.8%). The chemotherapy benefit for invasive disease–free survival varied with the combination of recurrence score and age (P=0.004), with some benefit of chemotherapy found in women 50 years of age or younger with a recurrence score of 16 to 25. CONCLUSIONS Adjuvant endocrine therapy and chemoendocrine therapy had similar efficacy in women with hormone-receptor–positive, HER2-negative, axillary node–negative breast cancer who had a midrange 21-gene recurrence score, although some benefit of chemotherapy was found in some women 50 years of age or younger.
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    Altered Expression of Telomere-Associated Genes in Leukocytes among BRCA1 and BRCA2 Carriers
    (Wiley, 2018) Tanaka, Hiromi; Phipps, Elizabeth A.; Wei, Ting; Wu, Xi; Goswami, Chirayu; Liu, Yunlong; Sledge, George W., Jr.; Mina, Lida; Herbert, Brittney-Shea; Medical and Molecular Genetics, School of Medicine
    Telomere dysfunction resulting from telomere shortening and deregulation of shelterin components has been linked to the pathogenesis of age-related disorders, including cancer. Recent evidence suggests that BRCA1/2 (BRCA1 and BRCA2) tumor suppressor gene products play an important role in telomere maintenance. Although telomere shortening has been reported in BRCA1/2 carriers, the direct effects of BRCA1/2 haploinsufficiency on telomere maintenance and predisposition to cancer development are not completely understood. In this study, we assessed the telomere-associated and telomere-proximal gene expression profiles in peripheral blood leukocytes from patients with a BRCA1 or BRCA2 mutation, compared to samples from sporadic and familial breast cancer individuals. We found that 25 genes, including TINF2 gene (a negative regulator of telomere length), were significantly differentially expressed in BRCA1 carriers. Leukocyte telomere length analysis revealed that BRCA1/2 carriers had relatively shorter telomeres than healthy controls. Further, affected BRCA1/2 carriers were well differentiated from unaffected BRCA1/2 carriers by the expression of telomere-proximal genes. Our results link BRCA1/2 haploinsufficiency to changes in telomere length, telomere-associated as well as telomere-proximal gene expression. Thus, this work supports the effect of BRCA1/2 haploinsufficiency in the biology underlying telomere dysfunction in cancer development. Future studies evaluating these findings will require a large study population.
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    Genome-Wide Association Study for Anthracycline-Induced Congestive Heart Failure
    (American Association for Cancer Research, 2017-01-01) Schneider, Bryan P.; Shen, Fei; Gardner, Laura; Radovich, Milan; Li, Lang; Miller, Kathy D.; Jiang, Guanglong; Lai, Dongbing; O’Neill, Anne; Sparano, Joseph A.; Davidson, Nancy E.; Cameron, David; Gradus-Pizlo, Irmina; Mastouri, Ronald A.; Suter, Thomas M.; Foroud, Tatiana; Sledge, George W., Jr.; Medicine, School of Medicine
    PURPOSE: Anthracycline-induced congestive heart failure (CHF) is a rare but serious toxicity associated with this commonly employed anticancer therapy. The ability to predict which patients might be at increased risk prior to exposure would be valuable to optimally counsel risk-to-benefit ratio for each patient. Herein, we present a genome-wide approach for biomarker discovery with two validation cohorts to predict CHF from adult patients planning to receive anthracycline. EXPERIMENTAL DESIGN: We performed a genome-wide association study in 3,431 patients from the randomized phase III adjuvant breast cancer trial E5103 to identify single nucleotide polymorphism (SNP) genotypes associated with an increased risk of anthracycline-induced CHF. We further attempted candidate validation in two independent phase III adjuvant trials, E1199 and BEATRICE. RESULTS: When evaluating for cardiologist-adjudicated CHF, 11 SNPs had a P value <10-5, of which nine independent chromosomal regions were associated with increased risk. Validation of the top two SNPs in E1199 revealed one SNP rs28714259 that demonstrated a borderline increased CHF risk (P = 0.04, OR = 1.9). rs28714259 was subsequently tested in BEATRICE and was significantly associated with a decreased left ventricular ejection fraction (P = 0.018, OR = 4.2). CONCLUSIONS: rs28714259 represents a validated SNP that is associated with anthracycline-induced CHF in three independent, phase III adjuvant breast cancer clinical trials.
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    Impact of African ancestry on the relationship between body mass index and survival in an early-stage breast cancer trial (ECOG-ACRIN E5103)
    (Wiley, 2022) Ballinger, Tarah J.; Jiang, Guanglong; Shen, Fei; Miller, Kathy D.; Sledge, George W., Jr.; Schneider, Bryan P.; Medicine, School of Medicine
    Background: African ancestry (AA) and obesity are associated with worse survival in early-stage breast cancer. Obesity disproportionately affects women of AA; however, the intersection between ancestry and obesity on breast cancer outcomes remains unclear. Methods: A total of 2854 patients in the adjuvant trial E5103 were analyzed. Genetic ancestry was determined using principal components from a genome-wide array. The impact of continuous or binary body mass index (BMI) on disease-free survival (DFS) and overall survival (OS) was evaluated by multivariable Cox proportional hazards models in AA patients and European ancestry (EA) patients. Results: There were 2471 EA patients and 383 AA patients. Higher BMI was significantly associated with worse DFS and OS only in AA patients (DFS hazard ratio [HR], 1.25; 95% CI, 1.07-1.46; OS HR, 1.38; 95% CI, 1.10-1.73), not in EA patients (DFS HR, 0.97; 95% CI, 0.90-1.05; OS HR, 1.03; 95% CI, 0.93-1.14). Severe obesity (BMI ≥40) was significantly associated with worse survival in AA patients (DFS HR, 2.04; 95% CI, 1.21-3.43; OS HR, 2.21; 95% CI, 1.03-4.75) but had no impact on that of EA patients. In the estrogen receptor-positive (ER+) and triple-negative breast cancer subgroups, BMI was significantly associated with worse outcomes only in those AA patients with ER+ disease. Within the AA group, BMI remained associated with worse survival regardless of the AA proportion. Conclusions: Higher BMI was statistically significantly associated with worse breast cancer outcomes in AA but not EA patients. This association was most significant for severe obesity and those with ER+ disease. These observations help define optimal populations for weight change interventions designed to affect disparities and survival in early-stage breast cancer. Lay summary: African ancestry and obesity are both risk factors for worse survival after early-stage breast cancer. Women of African descent are also disproportionately affected by obesity; however, it is unclear what impact body weight has on racial disparities in breast cancer. Data from a large phase 3 clinical trial in high-risk, early-stage breast cancer were used to determine how body weight affects survival outcomes in European versus African Americans. Study results demonstrate that a higher body mass index is associated with increased risk of breast cancer recurrence and worse survival in women of African ancestry but not in women of European ancestry.
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    Impact of Genetic Ancestry on Outcomes in ECOG-ACRIN-E5103
    (American Society of Clinical Oncology, 2017) Schneider, Bryan P.; Shen, Fei; Jiang, Guanglong; O'Neill, Anne; Radovich, Milan; Li, Lang; Gardner, Laura; Lai, Dongbing; Foroud, Tatiana; Sparano, Joseph A.; Sledge, George W., Jr.; Miller, Kathy D.; Medicine, School of Medicine
    Purpose: Racial disparity in breast cancer outcomes exists between African American and Caucasian women in the United States. We have evaluated the impact of genetically determined ancestry on disparity in efficacy and therapy-induced toxicity for breast cancer patients in the context of a randomized, phase III adjuvant trial. Patients and Methods: This study compared outcomes between 386 patients of African ancestry (AA) and 2473 patients of European ancestry (EA) in a randomized, phase III breast cancer trial; ECOG-ACRIN-E5103. The primary efficacy endpoint, invasive disease free survival (DFS) and clinically significant toxicities were compared including: anthracycline-induced congestive heart failure (CHF), taxane-induced peripheral neuropathy (TIPN), and bevacizumab-induced hypertension. Results: Overall, AAs had significantly inferior DFS (p=0.002; HR=1.5) compared with EAs. This was significant in the estrogen receptor-positive subgroup (p=0.03); with a similar, non-significant trend for those who had triple negative breast cancer (TNBC; p=0.12). AAs also had significantly more grade 3-4 TIPN (OR=2.9; p=2.4 ×10-11) and grade 3-4 bevacizumab-induced hypertension (OR=1.6; p=0.02), with a trend for more CHF (OR=1.8; p=0.08). AAs had significantly more dose reductions for paclitaxel (p=6.6 ×10-6). In AAs, dose reductions in paclitaxel had a significant negative impact on DFS (p=0.03); whereas in EAs, dose reductions did not impact outcome (p=0.35). Conclusion: AAs had inferior DFS with more clinically important toxicities in ECOG-ACRIN-E5103. The altered risk to benefit ratio for adjuvant breast cancer chemotherapy should lead to additional research with the focus centered on the impact of genetic ancestry on both efficacy and toxicity. Strategies to minimize dose reductions for paclitaxel, especially due to TIPN, are warranted for this population.
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    THE INDIANA CENTER FOR BREAST CANCER RESEARCH: PROGRESS REPORT
    (Office of the Vice Chancellor for Research, 2013-04-05) Nakshatri, Harikrishna; Sledge, George W., Jr.; Badve, Sunil; Bales, Casey; Gilley, David P.; Goswami, Chirayu; Wells, Clark D.; Guise, Theresa; Ziner, Kim W.
    The mission of IUPUI breast cancer center is to address prevention, early detection, and treatment of breast cancer through translational projects, supportive cores, and synergistic programs. This poster details our efforts improve resources for breast cancer research and efforts to develop multi-PI investigator proposals. The Signature Center Initiative has developed two web resources: the Breast Cancer Prognostics Database (BCDB) to study prognostic implications of genes of interest in publically available breast cancer databases and PROGmiR, a microRNA database. The BCDB can be used to study overall, recurrence free and metastasis free survival in large patient series. PROGmiR allows investigators to study the prognostic importance of microRNAs. PROGmiR has recently been published and has been accessed by investigators from several countries. The signature center has also devoted considerable efforts in developing tumor tissue resource. Tissue Bank includes a total sample of N = 500 cases with 30% non-Caucasian cases from Wishard Memorial Hospital. Currently 237 cases have been assembled into a Tissue Microarray with clinical and follow up data. The breast cancer center has funded three pilot projects. Drs. Clark Wells, S. Badve, and G. Sandusky are collaborating on the project: “Histologic Analysis of the Protein Levels of Amot130, AmotL1 and YAP in Normal, Hyperplastic and Invasive Breast Cancer Tissues”. This project is investigating localized protein expression in paraffin-embedded tissues to associate expression levels with disease subtype and patient outcome. Dr. David Gilley and his group are collaborating on the project: “Luminal mammary progenitors are a unique site of telomere dysfunction”. This project is investigating the relationship between telomere dysfunction and breast cancer tumorigenesis. In the third project, Dr. Theresa Guise will be investigating the mechanisms of cancer-associated cachexia. Several multi-PI proposals are under preparation and one proposal with Drs. Nakshatri and Kathy Miller as PIs is currently under review.
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    Race, Ethnicity, and Clinical Outcomes in Hormone Receptor-Positive, HER2-Negative, Node-Negative Breast Cancer in the Randomized TAILORx Trial
    (Oxford University Press, 2021-04-06) Albain, Kathy S.; Gray, Robert J.; Makower, Della F.; Faghih, Amir; Hayes, Daniel F.; Geyer, Charles E., Jr.; Dees, Elizabeth C.; Goetz, Matthew P.; Olson, John A., Jr.; Lively, Tracy; Badve, Sunil S.; Saphner, Thomas J.; Wagner, Lynne I.; Whelan, Timothy J.; Ellis, Matthew J.; Wood, William C.; Keane, Maccon M.; Gomez, Henry L.; Reddy, Pavan S.; Goggins, Timothy F.; Mayer, Ingrid A.; Brufsky, Adam M.; Toppmeyer, Deborah L.; Kaklamani, Virginia G.; Berenberg, Jeffrey L.; Abrams, Jeffrey; Sledge, George W., Jr.; Sparano, Joseph A.; Pathology and Laboratory Medicine, School of Medicine
    Background: Black race is associated with worse outcomes in early breast cancer. We evaluated clinicopathologic characteristics, the 21-gene recurrence score (RS), treatment delivered, and clinical outcomes by race and ethnicity among women who participated in the Trial Assigning Individualized Options for Treatment. Methods: The association between clinical outcomes and race (White, Black, Asian, other or unknown) and ethnicity (Hispanic vs non-Hispanic) was examined using proportional hazards models. All P values are 2-sided. Results: Of 9719 eligible women with hormone receptor-positive, HER2-negative, node-negative breast cancer, there were 8189 (84.3%) Whites, 693 (7.1%) Blacks, 405 (4.2%) Asians, and 432 (4.4%) with other or unknown race. Regarding ethnicity, 889 (9.1%) were Hispanic. There were no substantial differences in RS or ESR1, PGR, or HER2 RNA expression by race or ethnicity. After adjustment for other covariates, compared with White race, Black race was associated with higher distant recurrence rates (hazard ratio [HR] = 1.60, 95% confidence intervals [CI] = 1.07 to 2.41) and worse overall survival in the RS 11-25 cohort (HR = 1.51, 95% CI = 1.06 to 2.15) and entire population (HR = 1.41, 95% CI = 1.05 to 1.90). Hispanic ethnicity and Asian race were associated with better outcomes. There was no evidence of chemotherapy benefit for any racial or ethnic group in those with a RS of 11-25. Conclusions: Black women had worse clinical outcomes despite similar 21-gene assay RS results and comparable systemic therapy in the Trial Assigning Individualized Options for Treatment. Similar to Whites, Black women did not benefit from adjuvant chemotherapy if the 21-gene RS was 11-25. Further research is required to elucidate the basis for this racial disparity in prognosis.