Comparative Cardiovascular Safety of Gonadotropin-releasing Hormone Antagonists and Agonists Among Patients Diagnosed with Prostate Cancer: A Systematic Review and Meta-analysis of Real-world Evidence Studies.

BACKGROUND AND OBJECTIVE: Gonadotropin-releasing hormone (GnRH) antagonists and agonists are cornerstone treatments in prostate cancer. However, evidence regarding the comparative cardiovascular safety of these drugs from clinical trials is inconclusive. The objective of this study was to systematically assess the risk of adverse cardiovascular events of GnRH antagonists compared with GnRH agonists across real-world evidence studies. METHODS: We conducted a systematic search of PubMed, Embase, Cochrane Library, Scopus, and Web of Science (2008-2023). We included real-world evidence studies comparing the risk of cardiovascular outcomes of GnRH antagonists with those of GnRH agonists among patients with prostate cancer. We conducted a meta-analysis of effect estimates across studies at a low or moderate risk of bias, assessed via the Risk of Bias in Non-Randomized Studies of Interventions (ROBINS-I) tool, using random-effect models. KEY FINDINGS AND LIMITATIONS: Among ten included studies, four were classified as having a moderate and six as having a serious risk of bias. Across three studies at a moderate risk of bias in the primary analysis, degarelix was associated with an increased risk (pooled relative risk [RR]: 1.31, 95% confidence interval [CI]: 1.14-1.51) of major adverse cardiovascular events (MACEs). An augmented risk was observed in two studies among patients with a history of cardiovascular disease (pooled RR: 1.31, 95% CI: 1.11-1.56) compared with one study among patients without a history of cardiovascular disease (RR: 1.15, 95% CI: 0.83-1.59). CONCLUSIONS AND CLINICAL IMPLICATIONS: Real-world evidence studies indicate that degarelix, compared with GnRH agonists, is associated with a modest increased risk of MACEs, particularly among patients with a history of cardiovascular disease. However, residual confounding due to the treatment of high-risk patients with degarelix may account for these findings. Additional large studies with detailed data on tumor characteristics and cardiovascular risk factors are needed to confirm these findings. PATIENT SUMMARY: In this systematic evaluation of evidence among patients diagnosed with prostate cancer in routine care, degarelix was associated with higher cardiovascular adverse outcomes than gonadotropin-releasing hormone agonists.

The landscape of use of NCCN-guideline chemotherapy regimens in stage I-IIIA breast cancer in an integrated healthcare delivery system.

PURPOSE: The National Comprehensive Cancer Network (NCCN) guidelines recommend a variety of drug combinations with specific administration schedules for the treatment of early-stage breast cancer, allowing physicians to deliver treatments recognizing individual patient complexities, including comorbidities, and patient-physician preference. While use of guideline regimens has shifted over time, there is little data to describe changes in how treatment for early-stage breast cancer has evolved over time. METHODS: In a cohort of 34,109 women treated for stage I-IIIA breast cancer between 2006-2019 at Kaiser Permanente Northern California and Kaiser Permanente Washington, we present the changes in chemotherapy regimens over time, and explore use of NCCN-guideline regimens (GR), guideline regimens used when said regimens were not included in guidelines, referred to as time-discordant regimens (TDR), and non-guideline regimens (NGR). Results are presented by drug combination and over time. RESULTS: Among 12,506 women receiving chemotherapy, 77.4% (n = 9681) received GRs, 9.1% (n = 1140) received TDRs, and 13.5% (n = 1685) received NGRs. In 2006, AC-T (cyclophosphamide-doxorubicin, paclitaxel) was the most common regimen, with TC (cyclophosphamide-docetaxel) becoming the most prevalent by 2019. NGRs were more common in cyclophosphamide-methotrexate-5-fluorouracil (CMF); cyclophosphamide-doxorubicin-paclitaxel-trastuzumab (ACTH); and paclitaxel-trastuzumab (TH). The use of GR has increased over time (p-trend < 0.001), while use of NGR (both in terms of administration schedule and drug combination) and TDR have decreased, although patterns vary by drug combination. CONCLUSION: Chemotherapy delivery has changed markedly over time, with a move toward more use of GR. These data are important for understanding the landscape of chemotherapy delivery in community healthcare settings.

Risk factors for breast cancer subtypes by race and ethnicity: A scoping review of the literature.

Background: Breast cancer is comprised of distinct molecular subtypes. Studies have reported differences in risk factor associations with breast cancer subtypes, especially by tumor estrogen receptor (ER) status, but their consistency across racial and ethnic populations has not been comprehensively evaluated. Methods: We conducted a qualitative, scoping literature review using the Preferred Reporting Items for Systematic Reviews and Meta-analysis, extension for Scoping Reviews to investigate consistencies in associations between 18 breast cancer risk factors (reproductive, anthropometric, lifestyle, and medical history) and risk of ER-defined subtypes in women who self-identify as Asian, Black or African American, Hispanic or Latina, or White. We reviewed publications between January 1, 1990 and July 1, 2022. Etiologic heterogeneity evidence (convincing, suggestive, none, or inconclusive) was determined by expert consensus. Results: Publications per risk factor ranged from 14 (benign breast disease history) to 66 (parity). Publications were most abundant for White women, followed by Asian, Black or African American, and Hispanic or Latina women. Etiologic heterogeneity evidence was strongest for parity, followed by age at first birth, post-menopausal BMI, oral contraceptive use, and estrogen-only and combined menopausal hormone therapy. Evidence was limited for other risk factors. Findings were consistent across racial and ethnic groups, although the strength of evidence varied. Conclusion: The literature supports etiologic heterogeneity by ER for some established risk factors that are consistent across race and ethnicity groups. However, in non-White populations evidence is limited. Larger, more comparable data in diverse populations is needed to better characterize breast cancer etiologic heterogeneity.

Pre-diagnosis tea and coffee consumption and survival after a diagnosis of ovarian cancer: results from the Ovarian Cancer Association Consortium.

BACKGROUND: Tea and coffee are the most frequently consumed beverages in the world. Green tea in particular contains compounds with potential anti-cancer effects, but its association with survival after ovarian cancer is uncertain. METHODS: We investigated the associations between tea and coffee consumption before diagnosis and survival using data from 10 studies in the Ovarian Cancer Association Consortium. Data on tea (green, black, herbal), coffee and caffeine intake were available for up to 5724 women. We used Cox proportional hazards regression to estimate adjusted hazard ratios (aHR) and 95% confidence intervals (CI). RESULTS: Compared with women who did not drink any green tea, consumption of one or more cups/day was associated with better overall survival (aHR = 0.84, 95% CI 0.71-1.00, p-trend = 0.04). A similar association was seen for ovarian cancer-specific survival in five studies with this information (aHR = 0.81, 0.66-0.99, p-trend = 0.045). There was no consistent variation between subgroups defined by clinical or lifestyle characteristics and adjustment for other aspects of lifestyle did not appreciably alter the estimates. We found no evidence of an association between coffee, black or herbal tea, or caffeine intake and survival. CONCLUSION: The observed association with green tea consumption before diagnosis raises the possibility that consumption after diagnosis might improve patient outcomes.

Neighborhood Archetypes and Cardiovascular Health in Black Breast Cancer Survivors.

Background: Maintaining cardiovascular health (CVH) is critical for breast cancer (BC) survivors, particularly given the potential cardiotoxic effects of cancer treatments. Poor CVH among Black BC survivors may be influenced by various area-level social determinants of health, yet the impact of neighborhood archetypes in CVH among this population remains understudied. Objectives: This study aimed to characterize the neighborhood archetypes where Black BC survivors resided at diagnosis and evaluate their associations with CVH. Methods: We assessed CVH 24 months post-diagnosis in 713 participants diagnosed between 2012 and 2017 in the Women's Circle of Health Follow-Up Study, a population-based study of Black BC survivors in New Jersey. Neighborhood archetypes, identified via latent class analysis based on 16 social and built environment features, were categorized into tertiles. Associations between neighborhood archetypes and CVH scores were estimated using polytomous logistic regression. Results: CVH scores were assessed categorically (low, moderate, and optimal) and as continuous variables. On average, Black BC survivors achieved only half of the recommended score for optimal CVH. Among the 4 identified archetypes, women in the Mostly Culturally Black and Hispanic/Mixed Land Use archetype showed the lowest CVH scores. Compared to this archetype, Black BC survivors in the Culturally Diverse/Mixed Land Use archetype were nearly 3 times as likely to have optimal CVH (relative risk ratio: 2.92; 95% CI: 1.58-5.40), with a stronger association observed in younger or premenopausal women. No significant CVH differences were noted for the other 2 archetypes with fewer built environment features. Conclusions: Neighborhood archetypes, integrating social and built environment factors, may represent crucial targets for promoting CVH among BC survivors.

Patient characteristics associated with delayed time to adjuvant chemotherapy among women treated for stage I-IIIA breast cancer.

For patients with breast cancer, delays in chemotherapy initiation have been adversely associated with recurrence and survival. We evaluated patient-level factors associated with delayed chemotherapy initiation, from both diagnosis and surgery, in a community-based cohort of women with early-stage breast cancer. For the Optimal Breast Cancer Chemotherapy Dosing study, we identified a cohort of 34,109 women diagnosed with stage I-IIIA breast cancer at two U.S. integrated healthcare delivery systems between 2004 and 2019. We used logistic regression to calculate odds ratios (OR) and 95% confidence intervals (CI) to identify patient factors associated with delays in chemotherapy initiation after diagnosis (≥90 days) and surgery (≥60 days). Among 10,968 women receiving adjuvant chemotherapy, 21.1% experienced delays in chemotherapy initiation after diagnosis and 21.3% after surgery. Older age, non-Hispanic Black and Hispanic race and ethnicity, and ER+ and/or PR+ disease were associated with increased likelihood of delays to chemotherapy initiation after diagnosis and surgery. People diagnosed in 2012-2019 (vs. 2005-2011), with a higher grade and larger tumor size were less likely to experience delays. Other factors were associated with a higher likelihood of delays specifically from diagnosis (earlier stage, mastectomy vs. breast-conserving surgery), or surgery (higher comorbidity, increased nodal number). Women diagnosed with breast cancer who were at highest risk of progression and recurrence were less likely to experience delays in chemotherapy initiation after diagnosis and surgery. Understanding reasons for chemotherapy delays beyond patient factors may be potentially important to reduce risk of breast cancer recurrence and progression.

Risk factors for breast cancer subtypes by race and ethnicity: A scoping review.

BACKGROUND: Breast cancer is comprised of distinct molecular subtypes. Studies have reported differences in risk factor associations with breast cancer subtypes, especially by tumor estrogen receptor (ER) status, but their consistency across racial and ethnic populations has not been comprehensively evaluated. METHODS: We conducted a qualitative, scoping literature review using the Preferred Reporting Items for Systematic Reviews and Meta-analysis, extension for Scoping Reviews to investigate consistencies in associations between 18 breast cancer risk factors (reproductive, anthropometric, lifestyle, and medical history) and risk of ER-defined subtypes in women who self-identify as Asian, Black or African American, Hispanic or Latina, or White. We reviewed publications between January 1, 1990 and July 1, 2022. Etiologic heterogeneity evidence (convincing, suggestive, none, or inconclusive) was determined by expert consensus. RESULTS: Publications per risk factor ranged from 14 (benign breast disease history) to 66 (parity). Publications were most abundant for White women, followed by Asian, Black or African American, and Hispanic or Latina women. Etiologic heterogeneity evidence was strongest for parity, followed by age at first birth, post-menopausal BMI, oral contraceptive use, and estrogen-only and combined menopausal hormone therapy. Evidence was limited for other risk factors. Findings were consistent across racial and ethnic groups, although the strength of evidence varied. CONCLUSION: The literature supports etiologic heterogeneity by ER for some established risk factors that are consistent across race and ethnicity groups. However, in non-White populations evidence is limited. Larger, more comparable data in diverse populations is needed to better characterize breast cancer etiologic heterogeneity.

Patient characteristics associated with intended non-guideline chemotherapy in women with stage I-IIIA breast cancer.

BACKGROUND: Guidelines informing chemotherapy regimen selection are based on clinical trials with participants who do not necessarily represent general populations with breast cancer. Understanding who receives non-guideline regimens is important to understanding real-world chemotherapy administration and how it relates to patient outcomes. METHODS: Using data from the Optimal Breast Cancer Chemotherapy Dosing (OBCD) cohort study, based at Kaiser Permanente Northern California (2006-2019) and Kaiser Permanente Washington (2004-2015), we use logistic regression to examine the associations between patient characteristics and receipt of non-NCCN-guideline chemotherapy among 11,293 women with primary stage I-IIIA breast cancer receiving chemotherapy. RESULTS: Use of non-guideline regimens was strongly associated with several factors, including older age (OR≥80 vs 18-39: 5.25, 95%CI: 3.06-9.00)(p-trend=0.002) and human epidermal growth factor-2 status (ORHER2+ vs HER2-: 3.44; 95%CI: 3.06-3.87) and was less likely in women with larger tumor size (OR>5cm vs 0.1-≤0.5cm: 0.56; 95%CI: 0.36-0.87)(p-trend=0.01) and diagnosed in later years (OR2012-2019 vs 2005-2011: 0.80; 95%CI: 0.71-0.90). Factors associated varied by type of non-guideline regimen. For example, women with comorbidity and older age were more likely to receive non-guideline drug combinations in particular, while women with larger tumor size were less likely to receive non-guideline administration schedules. CONCLUSIONS: Non-guideline chemotherapy regimens are more likely in certain patient populations. IMPACT: These associations highlight that vulnerable patient populations may be less likely to receive guideline care and thus real-world studies are essential to understanding how the use of non-guideline regimens impacts patient outcomes in these groups.

Trends in chemotherapy use for early-stage breast cancer from 2006 to 2019.

BACKGROUND: Little is known about how use of chemotherapy has evolved in breast cancer patients. We therefore describe chemotherapy patterns for women with stage I-IIIA breast cancer in the Optimal Breast Cancer Chemotherapy Dosing (OBCD) Study using data from KPNC (Kaiser Permanente Northern California) and KPWA (Kaiser Permanente Washington). FINDINGS: Among 33,670 women, aged 18 + y, diagnosed with primary stage I-IIIA breast cancer at KPNC and KPWA from 2006 to 2019, we explored patterns of intravenous chemotherapy use, defined here as receipt of intravenous cytotoxic drugs and/or anti-HER2 therapies. We evaluated trends in chemotherapy receipt, duration over which chemotherapy was received, and number of associated infusion visits. In secondary analyses, we stratified by receipt of anti-HER2 therapies (trastuzumab and/or pertuzumab), given their longer duration. 38.9% received chemotherapy intravenously, declining from 40.2% in 2006 to 35.6% in 2019 (p-trend < 0.001). Among 13,089 women receiving chemotherapy, neoadjuvant treatment increased (4.1-14.7%; p-trend < 0.001), as did receipt of anti-HER2 therapies (20.8-30.9%) (p-trend < 0.001). The average treatment duration increased (5.3 to 6.0 months; p-trend < 0.001), as did the number of infusion visits (10.8 to 12.5; p-trend < 0.001). For those receiving anti-HER2 therapies, treatment duration and average number of visits decreased; among those not receiving anti-HER2 therapies, number of visits increased, with no change in duration. CONCLUSIONS: While the prevalence of chemotherapy receipt has decreased over time, the use of neoadjuvant chemotherapy has increased, as has use of anti-HER2 therapies; duration and number of administration visits have also increased. Understanding these trends is useful to inform clinical and administrative planning.

Racial and ethnic differences in epithelial ovarian cancer risk: an analysis from the Ovarian Cancer Association Consortium.

Limited estimates exist on risk factors for epithelial ovarian cancer (EOC) in Asian, Hispanic, and Native Hawaiian/Pacific Islander women. Participants in this study included 1734 Asian (n = 785 case and 949 control participants), 266 Native Hawaiian/Pacific Islander (n = 99 case and 167 control participants), 1149 Hispanic (n = 505 case and 644 control participants), and 24 189 White (n = 9981 case and 14 208 control participants) from 11 studies in the Ovarian Cancer Association Consortium. Logistic regression models estimated odds ratios (ORs) and 95% CIs for risk associations by race and ethnicity. Heterogeneity in EOC risk associations by race and ethnicity (P ≤ .02) was observed for oral contraceptive (OC) use, parity, tubal ligation, and smoking. We observed inverse associations with EOC risk for OC use and parity across all groups; associations were strongest in Native Hawaiian/Pacific Islander and Asian women. The inverse association for tubal ligation with risk was most pronounced for Native Hawaiian/Pacific Islander participants (odds ratio (OR) = 0.25; 95% CI, 0.13-0.48) compared with Asian and White participants (OR = 0.68 [95% CI, 0.51-0.90] and OR = 0.78 [95% CI, 0.73-0.85], respectively). Differences in EOC risk factor associations were observed across racial and ethnic groups, which could be due, in part, to varying prevalence of EOC histotypes. Inclusion of greater diversity in future studies is essential to inform prevention strategies. This article is part of a Special Collection on Gynecological Cancers.

CD163+ macrophages in the triple-negative breast tumor microenvironment are associated with improved survival in the Women's Circle of Health Study and the Women's Circle of Health Follow-Up Study.

BACKGROUND: Tumor-associated macrophages (TAMs) are a prominent immune subpopulation in the tumor microenvironment that could potentially serve as therapeutic targets for breast cancer. Thus, it is important to characterize this cell population across different tumor subtypes including patterns of association with demographic and prognostic factors, and breast cancer outcomes. METHODS: We investigated CD163+ macrophages in relation to clinicopathologic variables and breast cancer outcomes in the Women's Circle of Health Study and Women's Circle of Health Follow-up Study populations of predominantly Black women with breast cancer. We evaluated 611 invasive breast tumor samples (507 from Black women, 104 from White women) with immunohistochemical staining of tissue microarray slides followed by digital image analysis. Multivariable Cox proportional hazards models were used to estimate hazard ratios for overall survival (OS) and breast cancer-specific survival (BCSS) for 546 cases with available survival data (median follow-up time 9.68 years (IQR: 7.43-12.33). RESULTS: Women with triple-negative breast cancer showed significantly improved OS in relation to increased levels of tumor-infiltrating CD163+ macrophages in age-adjusted (Q3 vs. Q1: HR = 0.36; 95% CI 0.16-0.83) and fully adjusted models (Q3 vs. Q1: HR = 0.30; 95% CI 0.12-0.73). A similar, but non-statistically significant, association was observed for BCSS. Macrophage infiltration in luminal and HER2+ tumors was not associated with OS or BCSS. In a multivariate regression model that adjusted for age, subtype, grade, and tumor size, there was no significant difference in CD163+ macrophage density between Black and White women (RR = 0.88; 95% CI 0.71-1.10). CONCLUSIONS: In contrast to previous studies, we observed that higher densities of CD163+ macrophages are independently associated with improved OS and BCSS in women with invasive triple-negative breast cancer. Trial registration Not applicable.

Integrative multi-omics analyses to identify the genetic and functional mechanisms underlying ovarian cancer risk regions.

To identify credible causal risk variants (CCVs) associated with different histotypes of epithelial ovarian cancer (EOC), we performed genome-wide association analysis for 470,825 genotyped and 10,163,797 imputed SNPs in 25,981 EOC cases and 105,724 controls of European origin. We identified five histotype-specific EOC risk regions (p value <5 × 10-8) and confirmed previously reported associations for 27 risk regions. Conditional analyses identified an additional 11 signals independent of the primary signal at six risk regions (p value <10-5). Fine mapping identified 4,008 CCVs in these regions, of which 1,452 CCVs were located in ovarian cancer-related chromatin marks with significant enrichment in active enhancers, active promoters, and active regions for CCVs from each EOC histotype. Transcriptome-wide association and colocalization analyses across histotypes using tissue-specific and cross-tissue datasets identified 86 candidate susceptibility genes in known EOC risk regions and 32 genes in 23 additional genomic regions that may represent novel EOC risk loci (false discovery rate <0.05). Finally, by integrating genome-wide HiChIP interactome analysis with transcriptome-wide association study (TWAS), variant effect predictor, transcription factor ChIP-seq, and motifbreakR data, we identified candidate gene-CCV interactions at each locus. This included risk loci where TWAS identified one or more candidate susceptibility genes (e.g., HOXD-AS2, HOXD8, and HOXD3 at 2q31) and other loci where no candidate gene was identified (e.g., MYC and PVT1 at 8q24) by TWAS. In summary, this study describes a functional framework and provides a greater understanding of the biological significance of risk alleles and candidate gene targets at EOC susceptibility loci identified by a genome-wide association study.

Methodology for Using Real-World Data From Electronic Health Records to Assess Chemotherapy Administration in Women With Breast Cancer.

PURPOSE: Identification of patients' intended chemotherapy regimens is critical to most research questions conducted in the real-world setting of cancer care. Yet, these data are not routinely available in electronic health records (EHRs) at the specificity required to address these questions. We developed a methodology to identify patients' intended regimens from EHR data in the Optimal Breast Cancer Chemotherapy Dosing (OBCD) study. METHODS: In women older than 18 years, diagnosed with primary stage I-IIIA breast cancer at Kaiser Permanente Northern California (2006-2019), we categorized participants into 24 drug combinations described in National Comprehensive Cancer Network guidelines for breast cancer treatment. Participants were categorized into 50 guideline chemotherapy administration schedules within these combinations using an iterative algorithm process, followed by chart abstraction where necessary. We also identified patients intended to receive nonguideline administration schedules within guideline drug combinations and nonguideline drug combinations. This process was adapted at Kaiser Permanente Washington using abstracted data (2004-2015). RESULTS: In the OBCD cohort, 13,231 women received adjuvant or neoadjuvant chemotherapy, of whom 10,213 (77%) had their intended regimen identified via the algorithm, 2,416 (18%) had their intended regimen identified via abstraction, and 602 (4.5%) could not be identified. Across guideline drug combinations, 111 nonguideline dosing schedules were used, alongside 61 nonguideline drug combinations. A number of factors were associated with requiring abstraction for regimen determination, including: decreasing neighborhood household income, earlier diagnosis year, later stage, nodal status, and human epidermal growth factor receptor 2 (HER2)+ status. CONCLUSION: We describe the challenges and approaches to operationalize complex, real-world data to identify intended chemotherapy regimens in large, observational studies. This methodology can improve efficiency of use of large-scale clinical data in real-world populations, helping answer critical questions to improve care delivery and patient outcomes.

Comparing patient-reported outcomes and lifestyle factors before and after the COVID-19 pandemic among Black and Hispanic breast cancer survivors in New Jersey.

PURPOSE: The impact of the COVID-19 pandemic restrictions in the US since March 2020 on cancer survivorship among Black and Hispanic breast cancer (BC) survivors remains largely unknown. We aimed to evaluate associations of the pandemic with participant characteristics, patient-reported outcomes (PROs), and lifestyle factors among Black and Hispanic BC survivors in the Women's Circle of Health Follow-Up Study and the New Jersey BC Survivors Study. METHODS: We included 447 Black (npre = 364 and npost = 83) and 182 Hispanic (npre = 102 and npost = 80) BC survivors who completed a home interview approximately 24 months post-diagnosis between 2017 and 2023. The onset of the pandemic was defined as March 2020. The association of the pandemic with binary outcomes was estimated using robust Poisson regression models. RESULTS: Hispanic and Black BC survivors recruited after the onset of the pandemic reported higher socioeconomic status and fewer comorbidities. Black women in the post-pandemic group reported a higher prevalence of clinically significant sleep disturbance (prevalence ratio (PR) 1.43, 95% CI 1.23, 1.68), lower sleep efficiency, and lower functional well-being, compared to the pre-pandemic group. Hispanic women were less likely to report low health-related quality of life (vs. high; PR 0.62, 95% CI 0.45, 0.85) after the onset of the pandemic. CONCLUSIONS: Ongoing research is crucial to untangle the impact of the pandemic on racial and ethnic minorities participating in cancer survivorship research, as well as PROs and lifestyle factors. IMPLICATIONS FOR CANCER SURVIVORS: This study highlights the importance of considering the impact of the pandemic in all aspects of research, including the interpretation of findings.

Large-scale genome-wide association study of 398,238 women unveils seven novel loci associated with high-grade serous epithelial ovarian cancer risk.

Background: Nineteen genomic regions have been associated with high-grade serous ovarian cancer (HGSOC). We used data from the Ovarian Cancer Association Consortium (OCAC), Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA), UK Biobank (UKBB), and FinnGen to identify novel HGSOC susceptibility loci and develop polygenic scores (PGS). Methods: We analyzed >22 million variants for 398,238 women. Associations were assessed separately by consortium and meta-analysed. OCAC and CIMBA data were used to develop PGS which were trained on FinnGen data and validated in UKBB and BioBank Japan. Results: Eight novel variants were associated with HGSOC risk. An interesting discovery biologically was finding that TP53 3'-UTR SNP rs78378222 was associated with HGSOC (per T allele relative risk (RR)=1.44, 95%CI:1.28-1.62, P=1.76×10-9). The optimal PGS included 64,518 variants and was associated with an odds ratio of 1.46 (95%CI:1.37-1.54) per standard deviation in the UKBB validation (AUROC curve=0.61, 95%CI:0.59-0.62). Conclusions: This study represents the largest GWAS for HGSOC to date. The results highlight that improvements in imputation reference panels and increased sample sizes can identify HGSOC associated variants that previously went undetected, resulting in improved PGS. The use of updated PGS in cancer risk prediction algorithms will then improve personalized risk prediction for HGSOC.

Novel breast cancer susceptibility loci under linkage peaks identified in African ancestry consortia.

BACKGROUND: Expansion of genome-wide association studies across population groups is needed to improve our understanding of shared and unique genetic contributions to breast cancer. We performed association and replication studies guided by a priori linkage findings from African ancestry (AA) relative pairs. METHODS: We performed fixed-effect inverse-variance weighted meta-analysis under three significant AA breast cancer linkage peaks (3q26-27, 12q22-23, and 16q21-22) in 9241 AA cases and 10 193 AA controls. We examined associations with overall breast cancer as well as estrogen receptor (ER)-positive and negative subtypes (193,132 SNPs). We replicated associations in the African-ancestry Breast Cancer Genetic Consortium (AABCG). RESULTS: In AA women, we identified two associations on chr12q for overall breast cancer (rs1420647, OR = 1.15, p = 2.50×10-6; rs12322371, OR = 1.14, p = 3.15×10-6), and one for ER-negative breast cancer (rs77006600, OR = 1.67, p = 3.51×10-6). On chr3, we identified two associations with ER-negative disease (rs184090918, OR = 3.70, p = 1.23×10-5; rs76959804, OR = 3.57, p = 1.77×10-5) and on chr16q we identified an association with ER-negative disease (rs34147411, OR = 1.62, p = 8.82×10-6). In the replication study, the chr3 associations were significant and effect sizes were larger (rs184090918, OR: 6.66, 95% CI: 1.43, 31.01; rs76959804, OR: 5.24, 95% CI: 1.70, 16.16). CONCLUSION: The two chr3 SNPs are upstream to open chromatin ENSR00000710716, a regulatory feature that is actively regulated in mammary tissues, providing evidence that variants in this chr3 region may have a regulatory role in our target organ. Our study provides support for breast cancer variant discovery using prioritization based on linkage evidence.

Assessment of breast cancer chemotherapy dose reduction in an integrated healthcare delivery system.

PURPOSE: Most cytotoxic drugs are dosed using body surface area (BSA), yet not all cancer patients receive the full BSA-determined dose. Prior work suggests that breast cancer patients who are obese are more likely to experience dose reduction than normal weight patients. However, the factors driving dose reduction remain unclear. METHODS: In 452 women diagnosed with stage I-IIIA primary breast cancer at Kaiser Permanente Northern California, we evaluated the association between obesity and dose reduction, and further explored other factors in relation to dose reduction, including various sociodemographic characteristics, tumor characteristics, and comorbidities. Study participants were a part of the Pathways Study, diagnosed between 2006 and 2013 and treated with cyclophosphamide + doxorubicin, followed by paclitaxel (ACT). Dose reduction was assessed using first cycle dose proportion (FCDP) and average relative dose intensity (ARDI), a metric of dose intensity over the course of chemotherapy. RESULTS: Overall, 8% of participants received a FCDP < 90% and 21.2% had an ARDI < 90%, with dose reduction increasing with body mass index. In adjusted logistic regression models, obese women had 4.1-fold higher odds of receiving an ARDI < 90% than normal weight women (95% CI: 1.9-8.9; p-trend = 0.0006). Increasing age was positively associated with an ADRI < 90%, as was the presence of comorbidity. Dose reduction was less common in later calendar years. CONCLUSION: Results offer insight on factors associated with chemotherapy dosing for a common breast cancer regimen. Larger studies are required to evaluate relevance to other regimens, and further work will be needed to determine whether dose reductions impact outcomes in obese women.

Evaluation of Algorithms Using Automated Health Plan Data to Identify Breast Cancer Recurrences.

BACKGROUND: We updated algorithms to identify breast cancer recurrences from administrative data, extending previously developed methods. METHODS: In this validation study, we evaluated pairs of breast cancer recurrence algorithms (vs. individual algorithms) to identify recurrences. We generated algorithm combinations that categorized discordant algorithm results as no recurrence [High Specificity and PPV (positive predictive value) Combination] or recurrence (High Sensitivity Combination). We compared individual and combined algorithm results to manually abstracted recurrence outcomes from a sample of 600 people with incident stage I-IIIA breast cancer diagnosed between 2004 and 2015. We used Cox regression to evaluate risk factors associated with age- and stage-adjusted recurrence rates using different recurrence definitions, weighted by inverse sampling probabilities. RESULTS: Among 600 people, we identified 117 recurrences using the High Specificity and PPV Combination, 505 using the High Sensitivity Combination, and 118 using manual abstraction. The High Specificity and PPV Combination had good specificity [98%, 95% confidence interval (CI): 97-99] and PPV (72%, 95% CI: 63-80) but modest sensitivity (64%, 95% CI: 44-80). The High Sensitivity Combination had good sensitivity (80%, 95% CI: 49-94) and specificity (83%, 95% CI: 80-86) but low PPV (29%, 95% CI: 25-34). Recurrence rates using combined algorithms were similar in magnitude for most risk factors. CONCLUSIONS: By combining algorithms, we identified breast cancer recurrences with greater PPV than individual algorithms, without additional review of discordant records. IMPACT: Researchers should consider tradeoffs between accuracy and manual chart abstraction resources when using previously developed algorithms. We provided guidance for future studies that use breast cancer recurrence algorithms with or without supplemental manual chart abstraction.

Advancing Social and Environmental Research in Cancer Registries Using Geomasking for Address-Level Data.

Understanding the social and environmental causes of cancer in the United States, particularly in marginalized communities, is a major research priority. Population-based cancer registries are essential for advancing this research, given their nearly complete capture of incident cases within their catchment areas. Most registries limit the release of address-level geocodes linked to cancer outcomes to comply with state health departmental regulations. These policies ensure patient privacy, uphold data confidentiality, and enhance trust in research. However, these restrictions also limit the conduct of high-quality epidemiologic studies on social and environmental factors that may contribute to cancer burden. Geomasking refers to computational algorithms that distort locational data to attain a balance between effectively "masking" the original address location while faithfully maintaining the spatial structure in the data. We propose that the systematic deployment of scalable geomasking algorithms could accelerate research on social and environmental contributions across the cancer continuum by reducing measurement error bias while also protecting privacy. We encourage multidisciplinary teams of registry officials, geospatial analysts, cancer researchers, and others engaged in this form of research to evaluate and apply geomasking procedures based on feasibility of implementation, accuracy, and privacy protection to accelerate population-based research on social and environmental causes of cancer.

Experiences and lessons learned from community-engaged recruitment for the South Asian breast cancer study in New Jersey during the COVID-19 pandemic.

BACKGROUND: South Asians are a rapidly growing population in the United States. Breast cancer is a major concern among South Asian American women, who are an understudied population. We established the South Asian Breast Cancer (SABCa) study in New Jersey during early 2020 to gain insights into their breast cancer-related health attitudes. Shortly after we started planning for the study, the COVID-19 disease spread throughout the world. In this paper, we describe our experiences and lessons learned from recruiting study participants by partnering with New Jersey's community organizations during the COVID-19 pandemic. METHODS: We used a cross-sectional design. We contacted 12 community organizations and 7 (58%) disseminated our study information. However, these organizations became considerably busy with pandemic-related needs. Therefore, we had to pivot to alternative recruitment strategies through community radio, Rutgers Cancer Institute of New Jersey's Community Outreach and Engagement Program, and Rutgers Cooperative Extension's community health programs. We recruited participants through these alternative strategies, obtained written informed consent, and collected demographic information using a structured survey. RESULTS: Twenty five women expressed interest in the study, of which 22 (88%) participated. Nine (41%) participants learned about the study through the radio, 5 (23%) through these participants, 1 (4.5%) through a non-radio community organization, and 7 (32%) through community health programs. Two (9%) participants heard about the study from their spouse. All participants were born outside the US, their average age was 52.4 years (range: 39-72 years), and they have lived in the US for an average of 26 years (range: 5-51 years). CONCLUSION: Pivoting to alternative strategies were crucial for successful recruitment. Findings suggest the significant potential of broadcast media for community-based recruitment. Family dynamics and the community's trust in our partners also encouraged participation. Such strategies must be considered when working with understudied populations.