Ganz, Patricia A.

AbstractPrevious transcriptome‐wide association studies (TWAS) have identified breast cancer risk genes by integrating data from expression quantitative loci and genome‐wide association studies (GWAS), but analyses of breast cancer subtype‐specific associations have been limited. In this study, we conducted a TWAS using gene expression data from GTEx and summary statistics from the hitherto largest GWAS meta‐analysis conducted for breast cancer overall, and by estrogen receptor subtypes (ER+ and ER−). We further compared associations with ER+ and ER− subtypes, using a case‐only TWAS approach. We also conducted multigene conditional analyses in regions with multiple TWAS associations. Two genes, STXBP4 and HIST2H2BA, were specifically associated with ER+ but not with ER– breast cancer. We further identified 30 TWAS‐significant genes associated with overall breast cancer risk, including four that were not identified in previous studies. Conditional analyses identified single independent breast‐cancer gene in three of six regions harboring multiple TWAS‐significant genes. Our study provides new information on breast cancer genetics and biology, particularly about genomic differences between ER+ and ER− breast cancer.

Abstract Breast cancer survivorship guidelines recommend at least annual follow-up visits, yet the degree to which this occurs in clinical practice is uncertain. Claims data from a US commercial insurance database (OptumLabs) were used to identify women treated with curative intent surgery for newly diagnosed breast cancer between 2006 and 2014. In 25 035 women, median follow-up was 3 years. In the second year after surgery, 9.6% of the patients did not visit a primary care provider, an oncologist, or a surgeon (guideline-nonadherent). The guideline-nonadherent proportion increased from 7.8% in women diagnosed in 2006 to 12.2% in those diagnosed in 2014 (two-sided Wald P < .001). During years 2–6, guideline-nonadherence was also associated with older age, nonwhite race, no radiation, no chemotherapy, no endocrine therapy, and increasing time after surgery. There is a substantial and increasing rate of inadequate follow-up among breast cancer survivors. This has the potential to impair outcomes.

508 Background: PBI is an alternative to WBI, with potentially greater therapy (tx) compliance, and better integration with chemotherapy (CTX). NSABP B-39/RTOG 0413 clinical outcome results from 2018 did not show equivalence of PBI to WBI in local tumor control; PBI was statistically inferior, but with clinically small differences. PBI may be an acceptable alternative to WBI for some women. Understanding cosmesis and quality of life (QOL) treatment outcomes is important. Methods: B-39/0413 included a prospective QOL substudy with PRO evaluation of breast cancer treatment outcomes (cosmesis, function, pain) and fatigue using BCTOS and SF-36 vitality scales. Secondary QOL parameters included treatment related symptoms, perceived convenience of care, and the BPI pain scale. The study sample was stratified by CTX or not, as CTX is given before WBI but after PBI. PRO assessments occurred before randomization, the last day of adjuvant tx [CTX or radiation], 4 wks later, and 6, 12, 24, and 36 mo later. Primary aims included comparisons of change in fatigue from baseline to end of tx and equivalency of change in cosmesis from baseline to 36 mo for PBI v WBI. Separate analyses were done for CTX and non-CTX pts, controlling for axillary dissection. Each comparison used α=0.0125. Planned sample size was 964. Results: From 3-23-05 to 5-27-09, 975 pts were enrolled in the PRO study; 950 had follow-up data. 504 did not receive CTX and 446 received CTX. In non-CTX pts, PBI had less fatigue (p=0.011) and did not meet criteria for cosmesis equivalence (97.5% CI, -0.02 to 0.22; ∆=0.20). In CTX pts, PBI had worse fatigue (p=0.011) and equivalent cosmesis to WBI (97.5% CI, -0.09 to 0.21; ∆=0.24). In both groups, PBI pts reported less pain at end of tx. In non-CTX pts, PBI had more pain at 36 mo but in CTX pts, there was no difference. Convenience of care and treatment related symptom outcomes will be presented. Conclusions: In non-CTX pts, PBI is more convenient with less fatigue and slightly poorer cosmesis at 36 mo. Cosmesis was equivalent at 36 mo in CTX pts. Support: U10CA180868, -180822, UG1CA189867. Clinical trial information: NCT00103181.

Abstract Background: Conventional WBI after lumpectomy for early-stage breast cancer decreases ipsilateral breast tumor recurrence (IBTR), yielding comparable results to mastectomy. Accelerated PBI appears effective in reducing IBTR by treating only the tumor bed area. As the majority of IBTR occur at or in the vicinity of the tumor bed, we hypothesized that PBI would be as effective as WBI in controlling IBTR. The primary aim of NSABP B-39/RTOG 0413 was to determine if PBI provides equivalent local tumor control post lumpectomy compared to WBI in pts with early-stage breast cancer. The equivalency test was based on a 50% margin of increase in the hazard ratio (HR=1.5). Secondary endpoints included: overall survival (OS), recurrence-free interval (RFI), distant disease-free interval (DDFI), and toxicity. Methods: Eligible pts had lumpectomy with histologically-free margins and 0-3 positive axillary nodes. Pts were stratified by stage, menopausal status, hormone receptor status, and intent to receive chemotherapy and then randomized to PBI or WBI. PBI was 10 fractions of 3.4-3.85 Gy, given twice daily with either brachytherapy or 3D external beam radiation. WBI was 50 Gy in 2 Gy fractions given daily with a sequential boost to the surgical cavity. Follow-up was every 6 mos for 5 yrs and then annually. All analyses were by intent-to-treat. Results: From 3-21-05 to 4-16-13, 4216 pts were randomized: 2107 PBI; 2109 WBI. 61% were postmenopausal; 81% were hormone receptor-positive; 29% intended to receive chemotherapy. Stage distribution was: DCIS, 24%; invasive pN0, 65%; invasive pN1, 10%. As of 7-31-18, median follow-up was 10.2 yrs. There were 161 IBTRs as first events: 90 PBI v 71 WBI (HR 1.22; 90%CI 0.94-1.58). Per protocol-defined margin, to declare PBI and WBI equivalent regarding IBTR risk, the 90% CI for the observed HR had to lie entirely between 0.667 and 1.5. The percent of pts IBTR-free at 10 yrs was 95.2% PBI v 95.9% WBI. A statistically significant difference in the 10-yr RFI rate favored WBI (91.9% PBI v 93.4% WBI; HR 1.32; 95%CI 1.04-1.68; p=0.02). No statistically significant differences existed between PBI and WBI in DDFI (HR 1.31; 95%CI 0.91-1.91; p=0.15), OS (HR 1.10; 95%CI 0.90-1.35; p=0.35), or DFS (HR 1.12; 95%CI 0.98-1.29; p=0.11). Grade 3 toxicity was 9.6% PBI v 7.1% WBI, and grade 4-5 toxicity was 0.5% v 0.3%, respectively. Discussion: PBI did not meet the criteria for equivalence to WBI in controlling IBTR based on the upper limit of the hazard ratio confidence interval. However, the absolute difference in 10-yr rate of IBTR was <1% (4.8% PBI v 4.1% WBI). The risk of an RFI event was statistically significantly higher for PBI compared to WBI, but the absolute difference in 10-yr RFI rate was also small (8.1% PBI v 6.6% WBI). DDFI, OS, and DFS were not statistically different for PBI v WBI. Grade 3-5 toxicities, although low, were more common for PBI than WBI. The trial population was heterogeneous, ranging from Stage 0-2 breast cancer, and outcome by risk categories are being analyzed. Support: U10CA180868, -180822, UG1CA189867. Citation Format: Vicini FA, Cecchini RS, White JR, Julian TB, Arthur DW, Rabinovitch RA, Kuske RR, Parda DS, Ganz PA, Scheier MF, Winter KA, Paik S, Kuerer HM, Vallow LA, Pierce LJ, Mamounas EP, Costantino JP, Bear HD, Germaine I, Gustafson G, Grossheim L, Petersen IA, Hudes RS, Curran, Jr. WJ, Wolmark N. Primary results of NSABP B-39/RTOG 0413 (NRG Oncology): A randomized phase III study of conventional whole breast irradiation (WBI) versus partial breast irradiation (PBI) for women with stage 0, I, or II breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr GS4-04.

Abstract Background There are an estimated 1.4 million colorectal cancer (CRC) survivors in the United States. Research on endocrine and metabolic diseases over the long term in CRC survivors is limited. Obesity is a risk factor for CRC; thus it is of interest to investigate diseases that may share this risk factor, such as diabetes, for long-term health outcomes among CRC survivors. Methods A total of 7114 CRC patients were identified from the Utah Population Database and matched to a general population cohort of 25 979 individuals on birth year, sex, and birth state. Disease diagnoses (assessed over three time periods of 1–5 years, 5–10 years, and >10 years) were identified using electronic medical records and statewide ambulatory and inpatient discharge data. Cox proportional hazard models were used to estimate the risk of endocrine and metabolic disease. Results Across all three time periods, risks for endocrine and metabolic diseases were statistically significantly greater for CRC survivors compared with the general population cohort. At 1–5 years postdiagnosis, CRC survivors’ risk for diabetes mellitus with complications was statistically significantly elevated (hazard ratio [HR] = 1.36, 99% confidence interval [CI] = 1.09 to 1.70). CRC survivors also experienced a 40% increased risk of obesity at 1–5 years postcancer diagnosis (HR= 1.40, 99% CI= 1.66 to 2.18) and a 50% increased risk at 5–10 years postdiagnosis (HR = 1.50, 99% CI= 1.16 to 1.95). Conclusions Endocrine and metabolic diseases were statistically significantly higher in CRC survivors throughout the follow-up periods of 1–5 years, 5–10 years, and more than 10 years postdiagnosis. As the number of CRC survivors increases, understanding the long-term trajectory is critical for improved survivorship care.

Abstract Large-scale genome-wide association studies (GWAS) have identified approximately 35 loci associated with epithelial ovarian cancer (EOC) risk. The majority of GWAS-identified disease susceptibility variants are located in noncoding regions, and causal genes underlying these associations remain largely unknown. Here, we performed a transcriptome-wide association study to search for novel genetic loci and plausible causal genes at known GWAS loci. We used RNA sequencing data (68 normal ovarian tissue samples from 68 individuals and 6,124 cross-tissue samples from 369 individuals) and high-density genotyping data from European descendants of the Genotype-Tissue Expression (GTEx V6) project to build ovarian and cross-tissue models of genetically regulated expression using elastic net methods. We evaluated 17,121 genes for their cis-predicted gene expression in relation to EOC risk using summary statistics data from GWAS of 97,898 women, including 29,396 EOC cases. With a Bonferroni-corrected significance level of P < 2.2 × 10−6, we identified 35 genes, including FZD4 at 11q14.2 (Z = 5.08, P = 3.83 × 10−7, the cross-tissue model; 1 Mb away from any GWAS-identified EOC risk variant), a potential novel locus for EOC risk. All other 34 significantly associated genes were located within 1 Mb of known GWAS-identified loci, including 23 genes at 6 loci not previously linked to EOC risk. Upon conditioning on nearby known EOC GWAS-identified variants, the associations for 31 genes disappeared and three genes remained (P < 1.47 × 10−3). These data identify one novel locus (FZD4) and 34 genes at 13 known EOC risk loci associated with EOC risk, providing new insights into EOC carcinogenesis. Significance: Transcriptomic analysis of a large cohort confirms earlier GWAS loci and reveals FZD4 as a novel locus associated with EOC risk. Cancer Res; 78(18); 5419–30. ©2018 AACR.