Kushi, Lawrence H.

Abstract Background Opportunistic bilateral salpingectomy (OBS), the removal of fallopian tubes during hysterectomy or instead of tubal ligation, is recommended to reduce ovarian cancer risk. However, data on the effectiveness of prophylactic OBS is limited. Methods This population-based retrospective cohort included individuals aged 18–80 in Ontario, Canada, who underwent OBS or comparator surgeries (hysterectomy with ovarian and tubal conservation or tubal ligation) from 2011 to 2023. Individuals with gynecologic cancer before or within six months of surgery were excluded. Hazard ratios and 95% confidence intervals were estimated using Cox proportional hazards regression. Sensitivity analyses varied the time between surgery and cancer diagnosis to account for pre-existing serous tubal intraepithelial carcinomas. Results Among 196,839 individuals, 57,941 underwent OBS and 138,898 underwent comparator surgeries. 142 epithelial ovarian cancers were diagnosed (19 in the OBS group and 123 in the comparator surgery group). OBS was associated with reduced risk of any ovarian carcinoma, with an adjusted hazard ratio (aHR) of 0.60 (95% CI, 0.36 to 0.98). For serous ovarian carcinoma (high- and low-grade combined due to missing grade data), the aHR was 0.47 (95% CI, 0.22 to 0.99). Sensitivity analyses with 12- and 18-month intervals showed aHRs of 0.59 (95% CI, 0.35 to 0.99) and 0.60 (95% CI, 0.35 to 1.01) for all ovarian carcinomas, and 0.49 (95% CI, 0.23 to 1.01) and 0.47 (95% CI, 0.22 to 0.99) for serous ovarian carcinoma, respectively. Conclusions OBS was associated with reduced risk of ovarian carcinoma, supporting its role as a primary prevention strategy.

631 Background: Adolescent and young adult (AYA) women with breast cancer who have not completed their desired childbearing pre-diagnosis may be more likely to decline adjuvant endocrine therapy (ET) and/or to temporarily or permanently stop ET to pursue pregnancy. Fertility counseling and use of fertility preservation strategies (e.g., oocyte/embryo cryopreservation) might impact these decisions. Methods: In the Valuing Opinions and Insights from Cancer Experiences (VOICE) Study, we investigated whether use of fertility preservation strategies were associated with ET initiation and early discontinuation amongst AYAs with fertility concerns. Eligible females were diagnosed with stage 1–3 estrogen-receptor positive breast cancer at age 15-39 during 2013-2022 and responded to a survey in 2023-2024. Those who reported that they had not completed their desired family size or had been unsure about having completed their desired family size at the time of their cancer diagnosis were categorized as having had fertility concerns. ET initiation was defined as 2+ ET prescription fills within 18 months after diagnosis. Among ET initiators, we assessed early discontinuation (defined as lack of ET prescription fill over any 180 day period until 5 years after their first ET fill date). Due to inadequate power, we did not model the relationship between oocyte/embryo cryopreservation and ET initiation. However, we did have power to assess the association between oocyte/embryo cryopreservation and ET discontinuation using multivariable Cox regression to calculate Hazard Ratios (HR) and 95% Confidence Intervals (CI). HRs for discontinuation were adjusted for age at diagnosis, stage, study site, diagnosis year, income, and children before diagnosis (yes/no). Results: Among 518 AYA breast cancer survivors, 56% (N = 290) had fertility concerns at diagnosis. Of these 290, 41% had 1+ child before diagnosis, 90% received fertility counseling, 27% froze eggs or embryos, and 10% had 1+ child after diagnosis. The majority (89%) initiated ET. Among the 32 who did not initiate ET, 7 (22%) reported that fertility concerns impacted that decision. Oocyte/embryo cryopreservation was used by 26% of ET initiators and 34% of ET non-initiators. Among the 258 ET initiators, 89 (35%) discontinued ET early. Compared to those who did not use fertility preservation strategies, patients who froze oocytes/embryos were more likely to discontinue ET (HR 1.89; 95% CI 1.18–3.05). Among those who discontinued ET, 19% had 1+ child after diagnosis (compared to 2% among those who did not discontinue ET). Conclusions: This study confirmed prior studies showing that many AYAs with breast cancer have fertility concerns, and these concerns may impact decisions about ET. In our analysis, those who cryopreserved oocytes/embryos were more likely to discontinue ET early, and a higher proportion who discontinued ET had 1+ live birth after breast cancer.

1564 Background: Adolescent and young adult (AYA) females with early-stage ER-negative and/or HER2-positive breast cancer commonly receive chemotherapy to reduce risk of recurrence. Fertility concerns, counseling, and preservation may influence chemotherapy decisions and time to chemotherapy (TTC) initiation. Methods: We surveyed AYA survivors of stage I–III premenopausal ER-negative and/or HER2-positive breast cancer treated at Kaiser Permanente Northern and Southern California (2013-2022). Fertility concerns were defined as not having completed desired family size or being unsure about having completed desired family size at diagnosis. We summarized receipt of fertility counseling, receipt of chemotherapy, and use of oocyte/embryo cryopreservation for fertility preservation (FP). Among fertility-concerned patients who received chemotherapy, TTC (days from diagnosis) was assessed separately for neoadjuvant chemotherapy (NAC) vs for adjuvant chemotherapy (AdjC). Time to NAC was natural log–transformed and modeled with multivariable log-linear regression to estimate relative differences in TTC, adjusting for stage, study site, ER, HER2, age, and diagnosis year. Results: Of 363 respondents, 197 (54%) had fertility concerns at diagnosis; 183/197 (93%) received chemotherapy, similar to 153/166 (92%) among those without concerns (p=0.7). Of the concerned chemotherapy recipients, 45 (25%) saw a fertility specialist but did not pursue FP while 55 (30%) underwent FP. For the 112 fertility-concerned NAC recipients, FP was associated with longer TTC than no fertility specialist counseling (mean=41 vs. 30 days; adjusted ratio=1.39; 95% CI 1.15–1.69), whereas fertility specialist counseling without FP was not (mean= 31 vs. 30 days, adjusted ratio=1.04; 95% CI 0.86–1.25). For the 71 fertility-concerned AdjC recipients, TTC was similar for patients who did not see a fertility specialist (mean=63 days), those who froze oocytes/embryos (mean=65 days), and those who saw a fertility specialist but did not pursue FP (mean=69 days). Conclusions: In this AYA breast cancer cohort, there was no evidence that fertility concerns led patients to decline chemotherapy. FP was associated with a modest delay in NAC initiation (<2 weeks on average). Time to chemotherapy (TTC) among 183 AYA patients with ER− and/or HER2+ breast cancer and fertility concerns. Fertility-focused care N (n=183) Neoadjuvant chemotherapy (n=112) Mean TTC, days Relative difference in TTC, adjusted ratio (95%CI) Adjuvant chemotherapy (n=71) Mean TTC, days No fertility counseling from a specialist 83 (45%) 55 (49%) 29.6 Reference 28 (39%) 62.6 Received fertility counseling from a specialist No fertility preservation 45 (25%) 28 (25%) 30.7 1.04 (0.86,1.25) 17 (24%) 68.6 Fertility preservation 55 (30%) 29 (26%) 41.2 1.39 (1.15,1.69) 26 (37%) 64.6

Abstract Breast cancer (BC) is the most common cancer among female adolescents and young adults (AYAs; 15-39 years). While advances in treatment have improved survival, cardiovascular disease (CVD) can result from systemic therapies, and CVD is a leading cause of death in AYA cancer survivors. AYAs with BC face nearly a four-fold increased risk of CVD compared to their peers without cancer. However, data on the effects of systemic treatment on CVD in this population remains limited. We estimated risk of CVD in AYAs diagnosed with invasive BC (2006-2020), who survived ≥2 years, and were diagnosed and treated in the Kaiser Permanente (KP) Northern and Southern California. Patients were categorized by receipt of anthracycline-, alkylating-, HER2-, platinum-, and taxane-based therapies within 2 years of diagnosis. We examined the cumulative incidence of CVD starting 2 years post-diagnosis and used Cox proportional hazards regression to determine factors associated with CVD. Among 3,071 AYAs, 35.1% were non-Hispanic (NH) White, 31.6% were Hispanic, 18.3% were NH Asian, and 8.2% were NH Black. Most received systemic therapy (90.6%), including anthracycline- and alkylator without HER2-targeted therapy (41.9%) and HER2-targeted therapy without anthracycline (20.9%). Fewer AYAs received a taxane and alkylator (13.0%) or anthracycline with alkylator and taxane along with a HER2-targeting agent (6.4%). Mean follow-up after cancer diagnosis was 7.2 years (range: 2.0-17.5). The 10-year cumulative incidence of CVD was highest among AYAs who received anthracycline/alkylator/taxane/HER2-targeting therapy (19.6%), intermediate for those with anthracycline/alkylator without HER2-targeting therapy (13.0%) and those who received HER2-targeted therapy without anthracycline (14.6%), and lowest for those who received taxane/alkylator (7.3%). In the multivariable model adjusted for demographic factors and radiation, compared to taxane/alkylator, anthracycline/alkylator/taxane/HER2-targeting therapy (hazard ratio (HR)=2.63, 95% confidence interval (CI) 1.56-4.43); anthracycline/alkylator without HER2-targeting therapy (HR=1.75, CI 1.13-2.71); and HER2-targeting therapy without anthracycline (HR=2.13, CI 1.11-4.09) were associated with an increased risk of CVD. CVD risk was similar for taxane/alkylator and no systemic therapy. Other factors associated with higher risk of CVD included NH Black race/ethnicity (HR=1.90, CI 1.32-2.73 vs. NH White) and public health insurance (HR=1.67, CI 1.00-2.78 vs private). This study identifies AYA BC survivors at higher risk of CVD based on treatment regimens received, with highest risks found for those receiving anthracycline/alkylator/taxane/HER2 treatment combinations. In addition, AYAs of Black race/ethnicity and those with public health insurance experienced more CVD, underscoring the need for targeted interventions to mitigate these disparities. Citation Format: Theresa H. M. Keegan, Candice A. Sauder, Ann M. Brunson, Renata Abrahao, Anne C. Kirchhoff, Eric Haupt, Mallory Casperson, Ted Wun, Chun R. Chao, Andrew B. Smitherman, Hazel B. Nichols, Jessica Chubak, Erin E. Hahn, Lawrence H. Kushi, Kathryn J. Ruddy. Systemic therapy and cardiovascular disease in adolescent and young adult breast cancer survivors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5219.

This cohort study evaluates the reduction in risk of high-grade serous carcinoma among women undergoing opportunistic bilateral salpingectomy in Canada.

Importance Despite treatment advances, metastatic recurrence continues to be a leading cause of morbidity and mortality. Empirical data on the incidence and survival after metastatic recurrence remain limited, as cancer registries historically do not collect data on recurrence. Objective To estimate the cumulative incidence (CMI) of metastatic recurrence among adolescents and young adults diagnosed with earlier-stage disease and compare survival to those with metastatic disease at diagnosis. Design, Setting, Participants This was a retrospective cohort study of adolescents and young adults aged 15 to 39 years who were diagnosed with nonmetastatic cancers from 2006 to 2018. Adolescents and young adults were identified from the California Cancer Registry linked with statewide hospitalization, emergency department, and ambulatory surgery encounters from the California Department of Health Care Access and Information. Data were analyzed from December 2023 to June 2025. Exposures Cancer types, including melanoma, sarcoma, and breast, cervical, colorectal, testicular, and thyroid cancers. Main Outcomes and Measures Metastatic recurrence was identified using International Classification of Diseases, Ninth Revision, Clinical Modification, and Tenth Revision, Clinical Modification, metastatic disease codes at least 6 months after cancer diagnosis or from an underlying cancer cause of death. Follow-up was through December 31, 2020. Results Of a total of 48 406 adolescents and young adults (median [IQR] age at diagnosis, 33.0 [28.0-37.0] years; 67.4% female), 9.2% had metastatic disease at diagnosis, and 9.5% had metastatic recurrence. Among 43 935 adolescents and young adults who presented with nonmetastatic disease, the 5-year CMI of metastatic recurrences was highest among patients with sarcoma (24.5%; 95% CI, 22.6%-26.6%) and colorectal cancer (21.8%; 95% CI, 20.3%-23.4%) and intermediate for cervical (16.3%; 95% CI, 15.0%-17.6%) and breast (14.7%; 95% CI, 14.0%-15.4%) cancers. The CMI for metastatic recurrence increased with increasing stage at diagnosis, with 5-year CMIs higher than 30% for all stage III cancers (except thyroid). The 5-year CMI of metastatic recurrence also increased over time for cervical cancer (2006-2009: 12.7% [95% CI, 10.8%-14.8%]; 2015-2018: 20.4% [95% CI, 17.5%-23.6%]) and decreased for colorectal cancer (2006-2009: 24.4% [95% CI, 21.3%-27.6%]; 2015-2018: 19.2% [95% CI, 16.4%-22.2%]). Survival after metastatic recurrence was worse than metastatic disease at diagnosis for all cancer types, except for testicular and thyroid cancers. Conclusions and Relevance The findings from this cohort study highlight the overall burden of metastatic disease in adolescents and young adults, expanding the knowledge of metastatic recurrences that help improve care for adolescent and young adult survivors throughout the cancer survivorship spectrum.

Abstract Background Few studies have assessed the burden of chronic medical conditions in adolescent and young adult (AYA) cancer survivors. This study estimated the risk of these conditions among AYA survivors compared to a matched cohort without cancer. Methods This retrospective cohort study included 2‐year survivors ( n = 14,917) of 11 common AYA (15–39 years) cancers diagnosed at the integrated health care organizations of Kaiser Permanente (KP) Southern and Northern California during 2006–2020. A comparison cohort ( n = 149,164) without cancer (matched 10:1 by age, sex, calendar year, and KP site) was included. Cumulative incidence (CMI) accounting for death as a competing risk was calculated. Poisson regression estimated the incidence rate ratio (IRR) of each condition in cancer survivors versus the matched cohort, adjusting for age, sex, and race/ethnicity. Results The 5‐year CMI was highest for thyroid (17.4%), respiratory (6.6%), cardiovascular (5.0%), and liver (4.8%) diseases. At 10 years, the CMI of any condition was 39% in survivors versus 26% in the matched cohort. Survivors had a 2‐fold increased risk of being diagnosed with any medical condition (IRR, 2.0; 95% confidence interval [CI], 1.9–2.0) as well as two or more conditions (IRR, 2.3; 95% CI, 2.2–2.5). Risk was highest among survivors of hematologic cancers and those diagnosed with distant stage disease. Elevated risks were observed within all sociodemographic groups of this insured population. Conclusion AYAs with cancer had a higher risk of chronic medical conditions compared to those without cancer. Long‐term surveillance, risk mitigation through lifestyle modifications and effective disease management are crucial to reduce premature mortality.

Abstract Introduction: The purpose of this study is to evaluate the effectiveness of opportunistic salpingectomy (OS), a procedure that aims to remove only the fallopian tubes of general population risk women, for the prevention of epithelial ovarian cancer. Currently, the method of prevention for individuals at high risk of ovarian cancer involves a bilateral salpingo-oophorectomy (BSO), a procedure that removes both the fallopian tubes and ovaries. However, this procedure is not recommended for individuals of the general population, who make up about 80% of ovarian cancers, due to negative health implications to the cardiovascular and skeletal systems because of surgically induced menopause. The effectiveness of the OS in preventing ovarian cancers and how the procedure impacts the histotype distribution of ovarian cancers remains unknown. Study Methods: This study uses a population-based approach and a case-based approach to determine the effectiveness of OS and its impact on histotype distribution, respectively. For the population-based analysis, we will search through clinical databases to acquire cases of individuals who have had an OS and a tumor. A control population who have their fallopian tubes in-tact will also be acquired. A cox-proportional hazard analysis will be performed to determine the effectiveness of the procedure. Using pathological records, the case-based ascertainment of tumors from individuals who have had an OS will be selected and reviewed for histotype confirmation. Fallopian tubes of these patients will also be reviewed for precursor lesions. This cohort will be compared to a historical histotype distribution of ovarian cancers. Results: For the population-based approach, we have to date, identified less than five serous ovarian cancers in individuals who have had an OS (n=40, 477). A comparator surgery was used as a control and showed 21 cancers. For the case-based approach, we have partnered with 23 collaborating institutions from around the world to identify tumors in individuals who have had an OS. We have identified 26 epithelial ovarian cancers, with the most lethal gynecological histotype, high grade serous carcinoma (HGSC), accounting for 23.1% of the total proportion of epithelial ovarian cancer cases (n=6/26). This is significantly less than the historical histotype distribution of HGSC, which is 69.3% (Fisher’s exact test, p&lt;0.0001). One HGSC case had a precursor lesion called a serous tubal intraepithelial carcinoma (STIC) while reviewing fallopian tubes of this individual. TP53 mutation analysis on one HGSC tumor sample showed a frameshift mutation in TP53 (c229fs) with the tumor and the corresponding STIC staining negative for p53 protein expression by immunohistochemistry. Conclusion: This evidence demonstrates the effectiveness of opportunistic salpingectomy for the prevention of ovarian cancer and shows a histotype distribution shift, with the most lethal gynecological malignancy having a significant reduction in cases following the procedure. Citation Format: Ramlogan Sowamber, Alice J. Mei, Paramdeep Kaur, Julianne McLeod, Emily McKay, Alex Lukey, Jamie Bakkum-Gamez, Natalia Buza, Paul Cohen, Kyle Devins, Rhonda Farrell, Christine Garcia, Blake Gilks, Ellen Goode, Anjelica Hodgson, Brooke Howitt, Pei Hui, Jutta Huvila, Anthony Karnezis, Kianoosh Keyhanian, Mary Kinloch, Martin Köbel, Felix KF. Kommoss, Lawrence Kushi, Janice S. Kwon, Kara Long-Roche, Anais Malpica, Jessica N. McAlpine, Dianne Miller, Esther Oliva, Andrea Palicelli, Aleksandra Paliga, Carlos Parra-Herran, Celeste Leigh Pearce, Sharnel Perera, Jurgen M. Piek, Haiyan Qiu, Joseph Rabban, Robert Rome, Miranda Steenbeek, Rebecca Stone, Aline Talhouk, Kristin M. Tischer, Britton Trabert, Penelope M. Webb, John R. Zalcberg, Gillian E. Hanley, David G. Huntsman. Evaluating the effectiveness of opportunistic salpingectomy (OS) for the prevention of epithelial ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl):Abstract nr B045.

PURPOSE This pilot study examined the ability to operationalize the collection of real-world data to explore the potential use of real-world end points extracted from data from diverse health care data organizations and to assess how these relate to similar end points in clinical trials for immunotherapy-treated advanced non–small-cell lung cancer. PATIENTS AND METHODS Researchers from six organizations followed a common protocol using data from administrative claims and electronic health records to assess real-world end points, including overall survival (rwOS), time to next treatment, time to treatment discontinuation (rwTTD), time to progression, and progression-free survival, among patients with advanced non–small-cell lung cancer treated with programmed death 1/programmed death-ligand 1 inhibitors in real-world settings. Data sets included from 269 to 6,924 patients who were treated between January 2011 and October 2017. Results from contributors were anonymized. RESULTS Correlations between real-world intermediate end points (rwTTD and time to next treatment) and rwOS were moderate to high (range, 0.6 to 0.9). rwTTD was the most consistent end points as treatment detail was available in all data sets. rwOS at 1 year post–programmed death-ligand 1 initiation ranged from 40% to 57%. In addition, rwOS as assessed via electronic health records and claims data fell within the range of median OS values observed in relevant clinical trials. Data sources had been used extensively for research with ongoing data curation to assure accuracy and practical completeness before the initiation of this research. CONCLUSION These findings demonstrate that real-world end points are generally consistent with each other and with outcomes observed in randomized clinical trials, which substantiates the potential validity of real-world data to support regulatory and payer decision making. Differences observed likely reflect true differences between real-world and protocol-driven practices.