Nichols, Hazel B.

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.

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.

PURPOSE Survivors of adolescent and young adult (AYA)-onset cancers require comprehensive cancer surveillance care. Guidelines recommend 1-4 clinician visits annually for 5 years depending on stage and disease. The goal of this study was to identify factors associated with patterns of post-treatment primary and oncology care in a large cohort of survivors of AYA-onset cancers diagnosed within an integrated health care system. METHODS Patients diagnosed with cancer between 2006 and 2020 age 15-39 years were included. Surveillance visits were identified from electronic medical records 2-5 years after diagnosis. Multivariable logistic regression was used to assess associations with zero oncology specialty visits. RESULTS Of 7,925 survivors, 46% were Hispanic, 6% non-Hispanic Black, 11% non-Hispanic Asian, 35% non-Hispanic White, and 65% female. One-quarter had no oncology specialty visits in the first surveillance year rising to 38% in year 5; 31% had 3+ visits in the first year, declining to 13% in year 5. Over the surveillance period, 17% did not have any oncology specialty visits and 6% had no primary care or oncology visits. Those who were male (odds ratio [OR], 1.21 [95% CI, 1.02 to 1.45]), 20-24 years at diagnosis (OR, 1.58, 95% CI, 1.27 to 1.9; v 35 to 39), or non-Hispanic Black (OR, 1.38, 95% CI, 1.05 to 1.82; v non-Hispanic White) or had high-deductible commercial or Medicaid insurance (OR, 1.35, 95% CI, 1.15 to 1.59; OR, 1.42, 95% CI, 1.11 to 1.82, respectively; v no or low deductible commercial) were more likely to be in the 0-visit group for oncology specialty care. CONCLUSION Although the majority of this cohort received either primary or oncology specialty care, our study identifies those who may need tailored outreach for follow-up care. Continued research into development and testing of interventions to improve uptake of appropriate health care for survivors of AYA-onset cancers is critical.

PURPOSE There is strong evidence that leisure-time physical activity is protective against postmenopausal breast cancer risk but the association with premenopausal breast cancer is less clear. The purpose of this study was to examine the association of physical activity with the risk of developing premenopausal breast cancer. METHODS We pooled individual-level data on self-reported leisure-time physical activity across 19 cohort studies comprising 547,601 premenopausal women, with 10,231 incident cases of breast cancer. Multivariable Cox regression was used to estimate hazard ratios (HRs) and 95% CIs for associations of leisure-time physical activity with breast cancer incidence. HRs for high versus low levels of activity were based on a comparison of risk at the 90th versus 10th percentiles of activity. We assessed the linearity of the relationship and examined subtype-specific associations and effect modification across strata of breast cancer risk factors, including adiposity. RESULTS Over a median 11.5 years of follow-up (IQR, 8.0-16.1 years), high versus low levels of leisure-time physical activity were associated with a 6% (HR, 0.94 [95% CI, 0.89 to 0.99]) and a 10% (HR, 0.90 [95% CI, 0.85 to 0.95]) reduction in breast cancer risk, before and after adjustment for BMI, respectively. Tests of nonlinearity suggested an approximately linear relationship ( Pnonlinearity = .94). The inverse association was particularly strong for human epidermal growth factor receptor 2–enriched breast cancer (HR, 0.57 [95% CI, 0.39 to 0.84]; Phet = .07). Associations did not vary significantly across strata of breast cancer risk factors, including subgroups of adiposity. CONCLUSION This large, pooled analysis of cohort studies adds to evidence that engagement in higher levels of leisure-time physical activity may lead to reduced premenopausal breast cancer risk.

AbstractBackgroundFertility preservation (FP) may be underused after cancer diagnosis because of uncertainty around delays to cancer treatment and subsequent reproductive success.MethodsWomen aged 15 to 39 years diagnosed with cancer between 2004 and 2015 were identified from the North Carolina Central Cancer Registry. Use of assisted reproductive technology (ART) after cancer diagnosis between 2004 and 2018 (including FP) was assessed through linkage to the Society for Assisted Reproductive Technology. Linear regression was used to examine time to cancer treatment among women who did (n = 95) or did not (n = 469) use FP. Modified Poisson regression was used to estimate risk ratios (RRs) and 95% CIs for pregnancy and birth based on timing of ART initiation relative to cancer treatment (n = 18 initiated before treatment for FP vs n = 26 initiated after treatment without FP).ResultsThe median time to cancer treatment was 9 to 33 days longer among women who used FP compared with women who did not, matched on clinical factors. Women who initiated ART before cancer treatment may be more likely to have a live birth given pregnancy compared with women who initiated ART after cancer treatment (age‐adjusted RR, 1.47; 95% CI, 0.98‐2.23), though this may be affected by the more frequent use of gestational carriers in the former group (47% vs 20% of transfer cycles, respectively).ConclusionsFP delayed gonadotoxic cancer treatment by up to 4.5 weeks, a delay that would not be expected to alter prognosis for many women. Further study of the use of gestational carriers in cancer populations is warranted to better understand its effect on reproductive outcomes.

Abstract Introduction: Breast cancer treatments can impair fertility via direct gonadotoxicity (chemotherapy) as well as by introducing delays in childbearing that allow natural ovarian aging. Guidelines strongly recommend fertility counseling and consideration of fertility preservation techniques for premenopausal women who have not completed their desired childbearing at the time of cancer diagnosis. Prior studies have identified high rates of fertility concern but relatively low rates of fertility counseling and use of fertility preservation techniques. We sought to investigate rates of fertility counseling, use of fertility preservation techniques, and how fertility concerns impact cancer treatment decisions in a modern cohort of patients with breast cancer at a large academic medical center in the United States. Methods: All patients seen at Mayo Clinic Rochester with a new diagnosis (within the year prior) of stage 0-4 breast cancer were invited (by mail or in person) to participate in the Mayo Clinic Breast Registry. After informed consent, participants were asked to complete a baseline survey and annual follow-up surveys. On baseline and one-year surveys, patients were queried about desire for future children and fertility concerns. Nurse chart abstraction was used to collect information about tumor subtype, stage, and treatments received. We examined survey data from women diagnosed under the age of 50 who expressed an interest in having future biological children on either the baseline or year 1 survey between February 2015 and October 2020. Descriptive statistics were used to summarize the degree of fertility concern in this population, the impact of that concern on cancer treatment decisions, and steps taken to preserve fertility. Results: Between February 2015 and October 2020, 865 women under age 50 at diagnosis consented to the registry. Of these women, 627 completed a baseline and/or 1-year survey and 100 answered either “yes” or “unsure” to the question: “At the present time, do you wish to have any more biological children in the future?” on one or both surveys. Among the 100 women expressing interest in future child-bearing, 92% were white, 27% had node-positive and one had distant metastatic disease at diagnosis. The age at diagnosis ranged from 19 to 49 years, with a mean age of 33.8 years. Of the 75 who reported a desire for future children at baseline, 28% felt “somewhat concerned” about their future fertility and 40% felt “very concerned.” Of the 70 who reported a desire for future children on the year 1 survey, 17% felt “somewhat concerned” and 59% felt “very concerned.” For those “very concerned” about future fertility at year 1, 65% reported that this concern had a major impact on their treatment decisions. Often, that treatment modification entailed using endocrine therapy for less than 5 years; 52% of those who specified the type of treatment modification they had made indicated this option. Of note, six women who reported no desire for future biological children at baseline were “unsure” at year 1. At year 1, 93% of women recalled a discussion about fertility with their doctor prior to starting treatment, and 49% had taken steps to preserve fertility (32.5% with embryo cryopreservation, 20% with oocyte cryopreservation and 65% with a GnRH agonist; some selected multiple options). Conclusion: We found a reassuringly high rate of patient-reported fertility counseling and use of reproductive endocrinology technologies to preserve fertility in women who reported a desire for additional children at or soon after diagnosis with breast cancer. Consistent with prior studies, fertility concerns frequently impacted breast cancer treatment decisions. It is important to err on the side of inclusivity when providing fertility counseling because desire for fertility can change over time. Citation Format: Samantha Mannion, Alexandra Higgins, Elizabeth A Stewart, Zaraq Khan, Chandra Shenoy, Nicole Larson, Hazel B Nichols, H Irene Su, Ann H Partridge, Fergus J Couch, Janet E Olson, Kathryn Ruddy. Prevalence and impact of fertility concerns in young women with breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-11-02.

Abstract Background: Breast cancers in recently postpartum women may have worse outcomes, but studies examining tumor molecular features by pregnancy recency have shown conflicting results. Methods: This analysis used Carolina Breast Cancer Study data to examine clinical and molecular tumor features among women less than 50 years of age who were recently (≤10 years prior) or remotely (>10 years prior) postpartum, or nulliparous. Prevalence odds ratios (POR) and 95% confidence intervals (CI) were estimated using multivariable models. Results: Recently postpartum women (N = 618) were more frequently lymph node–positive [POR (95% CI): 1.66 (1.26–2.19)], estrogen receptor (ER)-negative [1.37 (1.02–1.83)], and IHC-based triple negative [1.57 (1.00–2.47)] compared with nulliparous (N = 360) women. Some differences were identified between recent versus remotely postpartum; smaller tumor size [0.67 (0.52–0.86)], p53 wildtype [0.53 (0.36–0.77)], and non–basal-like phenotype [0.53 (0.33–0.84)] were more common among recently postpartum. Recently postpartum (vs. nulliparous) had significant enrichment for adaptive immunity, T cells, B cells, CD8 T cells, activated CD8 T cells/natural killer (NK) cells, and T follicular helper (Tfh) cells and higher overall immune cell scores. These differences were attenuated in remotely (compared with recently) postpartum women. Conclusions: These results suggest a dominant effect of parity (vs. nulliparity) and a lesser effect of pregnancy recency on tumor molecular features, although tumor immune microenvironments were altered in association with pregnancy recency. Impact: Our study is unique in examining tumor immune microenvironment and RNA-based markers according to time since last childbirth. Future studies should examine the interplay between tumor features, postdiagnostic treatment, and outcomes among recently postpartum women. See related commentary by McDonald et al., p. 518

Abstract Background: Chemotherapy can damage the ovaries and cause amenorrhea, a surrogate for infertility. Young women often wish to understand and minimize their risk of chemotherapy-related amenorrhea (CRA). However, the incidence of CRA with regimens that do not include either an anthracycline or cyclophosphamide is poorly studied. For patients with HER-2 positive disease, these anthracycline and cyclophosphamide-sparing regimens (e.g., docetaxel-carboplatin) are common (in combination with Her-2 directed therapy) in both the neoadjuvant and adjuvant settings. Methods: Women diagnosed with breast cancer under age 50 and within the past 10 years were recruited through a Dr. Susan Love Research Foundation Army of Women e-mail blast. Those who provided their contact information were mailed a consent form and medical record authorization form. Participants then received a web-based survey that inquired about receipt of and type of chemotherapy (including date of last dose) and date of last menstrual period (LMP). Patient-reported LMP was compared to date of final chemotherapy dose to determine if the LMP occurred before (defined as “CRA”) or after the last chemotherapy dose. When available, medical record data was used in place of survey data regarding type of chemotherapy used. Exclusion criteria included: LMP prior to diagnosis date, receipt of multiple chemotherapy regimens or no chemotherapy regimens, receipt of ovarian suppression medications (which interfere with interpretation of menstrual data), surgical menopause prior to or at the same time as diagnosis, a cancer diagnosis more than 10 years prior, incomplete menstrual data on the survey, report of an unknown chemotherapy regimen, and no date available for the last chemotherapy dose without an LMP within a month prior to survey completion. Fisher Exact test was used to compare CRA rates between regimens. Rates after two anthracycline-sparing regimens (taxane/cyclophosphamide; taxane/carboplatin) were compared to rates after anthracycline/cyclophosphamide/taxane. Results: 273 women consented to participate in this study, 258 of whom filled out the web survey. 151 of them were eligible for this analysis with a median age at diagnosis of 41 (range 24-49) and a median time from last chemotherapy dose to survey of 62.5 months (range 2-138). CRA occurred in 51.2% of the 86 participants who received an anthracycline, cyclophosphamide, and a taxane, in 41.9% of the 43 participants who received only a taxane and cyclophosphamide (p=0.35), and in 13.3% of the 15 participants who received carboplatin with a taxane (p=0.01). When the 11 patients who were <12 months since last chemotherapy were excluded, CRA rates changed minimally. Age did not differ by regimen, but median time since chemotherapy was shorter in the taxane/carboplatin group (35 months vs. 68 months). Trastuzumab with or without pertuzumab was administered in 100% of patients who received carboplatin/taxane, in 23.3% of patients who received taxane and cyclophosphamide, and in 22.1% of patients who received anthracycline/cyclophosphamide/taxane. Conclusions: This study suggests that carboplatin/taxane may be substantially less gonadotoxic than cyclophosphamide-based (neo)adjuvant regimens. Further research is necessary to confirm these findings. Citation Format: Gast KC, Cathcart-Rake EJ, Norman A, Eshragi L, Obidegwu N, Yost K, Nichols HB, Rosenberg S, Su HI, Stewart E, Couch F, Vachon C, Ruddy KJ. Regimen-specific rates of chemotherapy-related amenorrhea in breast cancer survivors [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 P1-12-10.