Poorvu, Philip D.

Abstract Background Whether outcomes of germline BRCA1/2 (gBRCA1/2)-associated breast cancer differ compared with sporadic tumors is controversial. We explored the impact of gBRCA1/2 pathogenic variant (PV) status beyond established prognostic features. Methods We conducted 2 retrospective, matched cohort studies comparing gBRCA1/2 PV carriers and noncarriers with HER2-negative, stage I-III breast cancer (Clinical Outcomes Quality Database [COQD] cohort: 185 carriers, 555 noncarriers; Young Women’s Breast Cancer Study [YWS] cohort: 113 carriers, 226 noncarriers). Matching factors were age, stage, hormone receptor status, and year of diagnosis. Clinicopathological features, treatments, and survival outcomes were compared between carriers and noncarriers. Results Most patients in COQD had stage I-II disease (87.2%), and more carriers than noncarriers had genetic testing before diagnosis (33% vs 5.6%, P < .001). In YWS, 22.7% of patients had stage III tumors, and few were tested before diagnosis (14.8% of carriers vs 1.7% of noncarriers; P < .001). Carriers in COQD received chemotherapy more often than noncarriers (81.1 vs 67.0%, P < .001), including platinum (P = .010); the proportion was similar for carriers and noncarriers in YWS. After adjusting for chemotherapy, relapse-free survival was longer in carriers than noncarriers in COQD (adjusted hazard ratio = 0.48 [95% CI = 0.26 to 0.87], P = .016), and a favorable trend was observed for other survival outcomes in both cohorts. Triple-negative tumors appeared to drive the differences. Conclusions We observed a trend toward improved outcomes in gBRCA1/2 PV carriers compared with noncarriers. These findings suggest that carriers should not receive more aggressive treatment solely based on their germline mutation status. Prospective clinical trials in this population are warranted.

Abstract Background Breast cancer (BC) diagnosed during pregnancy or postpartum often presents with aggressive features, potentially influenced by hormonal, immunological, and tissue remodeling changes. Studies have suggested that postpartum BC may be associated with worse outcomes, though most evidence is retrospective and constrained by methodological limitations. This study evaluated associations between pregnancy history, recency of childbirth, and long-term outcomes in a prospective cohort of young patients with early-stage BC. Patients and Methods Patients aged ≤40 years with stage I–III BC enrolled in the Young Women’s Breast Cancer Study were categorized at diagnosis as nulligravid, nulliparous, pregnant, or parous (≤5 vs 5 to 10 years postpartum). Analyses were stratified by BC subtype (estrogen receptor-positive [ER+]/HER2−, HER2+, and triple-negative [TNBC]), with distant recurrence-free survival (DRFS) as the primary endpoint. Results Among 859 patients, 257 (29.9%) were nulligravid, 50 (5.8%) nulliparous, 37 (4.3%) pregnant, and 515 (60.0%) parous. Pregnant patients had proportionally more TNBC, nodal involvement, T3/T4, and grade 3 tumors. After 11.1 years median follow-up, pregnancy or postpartum status was not independently associated with DRFS in multivariable models adjusted for age, tumor characteristics, and treatment, with consistent findings across ER+/HER2−, HER2+, and TNBC subtypes. Sensitivity analyses, including further categorization of postpartum diagnoses (<2 vs 2 to 5 years), yielded consistent results. Conclusions Pregnancy history and recency of childbirth were not independently associated with long-term DRFS. Despite more aggressive features at diagnosis, patients diagnosed during or after pregnancy had comparable outcomes after adjustment, suggesting no adverse prognostic impact. Clinical trial registration NCT01468246 (https://clinicaltrials.gov/study/NCT01468246? term=NCT01468246&rank=1).

e12562 Background: Previous research has suggested that breast cancer (BC) diagnosed during pregnancy or the postpartum period exhibits more aggressive clinical features, possibly due to pregnancy-related hormonal changes, immune modulation, and alterations in the mammary microenvironment compared to nulligravid or women many years out from pregnancy. Emerging data have demonstrated potential worse outcomes for patients (pts) diagnosed in post-partum. This study evaluated the influence of timing of diagnosis in relation to pregnancy history and recency of childbirth on long-term outcomes in a modern cohort of young pts with early-stage BC. Methods: Pts with stage I–III BC age < 40y in the prospective Young Women’s Breast Cancer Study (YWBCS) were categorized at diagnosis as Nulligravid (no prior pregnancy), Nulliparous (prior pregnancy without live birth), Currently Pregnant, or Parous (subdivided by time since last childbirth: within 5 years [≤ 5y PP], and 5–10 years postpartum [5–10y PP]). Baseline characteristics and outcomes were compared across BC subtypes (estrogen receptor+/HER2- [ER+/HER2-], HER2+, and triple-negative BC [TNBC]). Prognostic analyses for distant recurrence-free survival (DRFS) used Cox models. Results: 859 pts were included, 257 (30%) nulligravid, 50 (6%) nulliparous, 37 (4%) pregnant, and 515 (60%) parous (348 [68%] were ≤5y PP, and 167 [32%] were 5–10y PP). Median follow-up was 133 (6–209) months. Median age at diagnosis was lower in nulligravid pts (33 vs. 35–38 years); T1 tumors were most common in pts >5y PP (62%), and N0 status was highest in nulligravid pts (64%) (all p < 0.0001). Pregnant pts had higher rates of TNBC (27%), and T3 tumors (14%), N1 status, N1 (41%), and Grade 3 (81%) tumors compared to other groups (all p < 0.0001). Overall, only tumor size (T2-T4 vs T1, HR 2.03; 95% CI 1.37–3.03) and nodal status (N1 vs N0, HR 2.22; 1.48–3.34; N2/3 vs N0, HR 3.23; 1.96-5.33) were independently associated with worse DRFS; pregnancy history was not: nulligravid + nulliparous pts had no significant differences in DRFS compared to Pregnant (HR 1.46; 0.75–2.86), Parous <5y PP (HR 0.86; 0.58–1.26), and Parous 5–10y PP (HR 0.89; 0.54–1.48). Subgroup analyses by BC subtype (Table) and sensitivity analyses (excluding currently pregnant pts or separating nulligravid and nulliparous pts) demonstrated no significant associations between pregnancy history and DRFS. Conclusions: In this cohort study of very young patients with early breast cancer with contemporary treatment including management of breast cancer during pregnancy, pregnancy history and recency of pregnancy were not independent predictors of long-term disease outcomes. DRFS results by subgroup. Pregnancy Group N (%) HR (95% CI) ER+/HER2- Nulligravid + Nulliparous 173 (38.1) Ref Pregnant 16 (3.5) 0.93 (0.32–2.70) Parous ≤5y PP 177 (39.0) 0.77 (0.45–1.29) Parous 5–10y PP 88 (19.4) 0.78 (0.39–1.53) HER2+ Nulligravid + Nulliparous 77 (30.8) Ref Pregnant 11 (4.4) 3.27 (0.80–13.38) Parous ≤5y PP 113 (45.2) 1.50 (0.60–3.75) Parous 5–10y PP 49 (19.6) 1.45 (0.45–4.66) TNBC Nulligravid + Nulliparous 56 (36.8) Ref Pregnant 10 (6.6) 1.92 (0.61–6.09) Parous ≤5y PP 57 (37.5) 0.68 (0.28–1.63) Parous 5–10y PP 29 (19.1) 1.16 (0.43–3.14)

BackgroundWeight gain after a breast cancer diagnosis is common and is associated with inferior outcomes. Young survivors may be especially susceptible to weight changes given the impact of treatment on menopausal status.MethodsThe authors identified women who were diagnosed with stage 0 to III breast cancer at age 40 years or younger between 2006 and 2016 from a multicenter prospective cohort. Self‐reported weight was collected at diagnosis and at 1 year and 3 years postdiagnosis. Tumor and treatment data were obtained from medical records and patient surveys. Multinomial logistic regression was used to identify the factors associated with weight gain (≥5%) or weight loss (≥5%) versus stable weight at 1 year and 3 years postdiagnosis.ResultsThe cohort included 956 women with a median age of 37 years at diagnosis. Mean weight significantly increased over time from 66.54 ± 14.85 kg at baseline to 67.33 ± 15.53 and 67.77 ± 14.65 kg at 1 year and 3 years, respectively (p ≤ .001 for both comparisons). The proportion of women experiencing ≥5% weight gain increased from 24.8% at 1 year to 33.9% at 3 years. At 1 year, less self‐perceived financial comfort, Black race, and stage III disease were significantly associated with weight gain; at 3 years, only less self‐perceived financial comfort remained significant. Baseline overweight or obesity was significantly associated with weight loss at both time points. Chemotherapy, endocrine therapy, and treatment‐related menopause were not associated with weight change.ConclusionsOne third of young breast cancer survivors experienced clinically significant weight gain 3 years after diagnosis; however, treatment‐related associations were not observed. Age‐appropriate lifestyle interventions, including the reduction of financial barriers, are needed to prevent weight gain in this high‐risk population.

524 Background: OFS is an important treatment component for premenopausal women with early and advanced HR+ BC and optimal efficacy may depend on complete E2 suppression with GnRHa, especially when combined with aromatase inhibitors (AI). However, standard assays lack sensitivity and accuracy at very low E2 concentrations, rendering detection of breakthrough ovarian function challenging. More informative data regarding endocrine effects of GnRHa are needed, particularly in young women who derive the most benefit from OFS yet more frequently had breakthrough E2 levels in the SOFT trial substudy, SOFT-EST. Methods: Using a prospective cohort study of women with BC diagnosed at age ≤ 40 years, we identified participants with stage I-IV HR+ BC on OFS treatment with leuprolide, goserelin or triptorelin and blood collected 1 year after diagnosis. Clinical data were obtained through surveys and medical records. Plasma estrogens were measured by liquid chromatography-tandem mass spectrometry, with a limit of detection of 0.2 pg/mL compared to 10 pg/mL with standard assays. We assessed the proportion of women on OFS with E2 > 2.72 pg/mL (10 pmol/L) and > 10 pg/mL. Patient characteristics, estrone (E1) and FSH levels, and disease-free (DFS) and overall survival (OS) were compared between those with and without elevated E2 using Fischer’s exact, Wilcoxon rank sum and log rank tests, respectively. Results: Of 84 patients who met inclusion criteria, 72 (86%) had stage I-III and 12 (14%) had stage IV BC; 25 were on OFS plus AI and 59 were on OFS plus tamoxifen (TAM). Median E2 was 3.1 pg/mL (range 0.2-30.9). 46 patients (55%) had E2 > 2.72 pg/mL, including 8 on AI and 38 on TAM; 4 (5%) had E2 > 10 pg/mL, including 1 on AI and 3 on TAM. Factors associated with E2 > 2.72 pg/mL were no prior chemotherapy, TAM and high E1 ( P ≤.05), but not age, BMI or GnRHa schedule (Table). After a median follow-up of 7 years, DFS events were seen in 6 patients with E2 > 2.72 pg/mL and 5 without ( P =.232); OS events were seen in 7 patients with E2 > 2.72 pg/mL and 5 without ( P =.608). Conclusions: More than half of young women with ER+ BC had E2 > 2.72 pg/mL on OFS, 91% of whom would not have been detected by standard assays. This may be an area amenable to intervention to improve outcomes in young women. However, larger studies are needed to elucidate the optimal E2 target on OFS and clinical implications of incomplete E2 suppression on ultrasensitive assays. [Table: see text]

Background Fear of cancer recurrence (FCR) is more intense in younger women. Because FCR is a powerful determinant of quality of life, identifying those at risk for persistently elevated FCR can inform timing of interventions. Methods A total of 965 women with stage 0 to stage III breast cancer enrolled in the Young Women's Breast Cancer Study, a prospective cohort of women diagnosed with breast cancer at age ≤40 years, completed the 3‐item Lasry Fear of Recurrence Index. Group‐based trajectory modeling was used to classify distinct FCR patterns from baseline through 5 years post‐diagnosis. Multinomial logistic regression was used to identify patient, disease, and treatment characteristics associated with each trajectory. Results Five FCR trajectories were identified with the majority of participants having moderate (33.1%) or high FCR (27.6%) that improved over time. A total of 6.9% participants had moderate FCR that worsened, whereas 21.7% had high FCR at baseline that remained high throughout. In the fully adjusted multinomial model, stages II and III (vs stage I) were associated with higher odds of being in the high/stable trajectory, whereas stage 0 (vs I), being financially comfortable (vs not comfortable), was associated with lower odds of being in the high/stable trajectory. White (vs non‐White) was associated with higher odds of being in a trajectory that improved over time. Conclusions Although FCR improves over time for many young women with breast cancer, approximately one‐third had FCR that was severe and did not improve or worsened over 5 years after diagnosis. Ongoing monitoring is warranted, with early referral to mental health professionals indicated for those at highest risk for unresolved FCR. Lay Summary Fear of recurrence is common among young women with breast cancer. The authors followed a large cohort of young women diagnosed with breast cancer when they were 40 years of age and younger, and found 5 distinct trajectories that show moderate and severe fears do not always improve over time and may require targeted mental health intervention.

PURPOSE Many patients and physicians remain concerned about the potential detrimental effects of pregnancy after breast cancer (BC) in terms of reproductive outcomes and maternal safety. This systematic review and meta-analysis aimed at providing updated evidence on these topics. METHODS A systematic literature review was conducted to identify studies including patients with a pregnancy after BC (PROSPERO number CRD42020158324). Likelihood of pregnancy after BC, their reproductive outcomes, and maternal safety were assessed. Pooled relative risks, odds ratios (ORs), and hazard ratios (HRs) with 95% CIs were calculated using random effects models. RESULTS Of 6,462 identified records, 39 were included involving 8,093,401 women from the general population and 112,840 patients with BC of whom 7,505 had a pregnancy after diagnosis. BC survivors were significantly less likely to have a subsequent pregnancy compared with the general population (relative risk, 0.40; 95% CI, 0.32 to 0.49). Risks of caesarean section (OR, 1.14; 95% CI, 1.04 to 1.25), low birth weight (OR, 1.50; 95% CI, 1.31 to 1.73), preterm birth (OR, 1.45; 95% CI, 1.11 to 1.88), and small for gestational age (OR, 1.16; 95% CI, 1.01 to 1.33) were significantly higher in BC survivors, particularly in those with previous chemotherapy exposure, compared with the general population. No significantly increased risk of congenital abnormalities or other reproductive complications were observed. Compared to patients with BC without subsequent pregnancy, those with a pregnancy had better disease-free survival (HR, 0.66; 95% CI, 0.49 to 0.89) and overall survival (HR, 0.56; 95% CI, 0.45 to 0.68). Similar results were observed after correcting for potential confounders and irrespective of patient, tumor, and treatment characteristics, pregnancy outcome, and timing of pregnancy. CONCLUSION These results provide reassuring evidence on the safety of conceiving in BC survivors. Patients' pregnancy desire should be considered a crucial component of their survivorship care plan.

12081 Background: Young women with breast cancer may be at increased risk for premature development of cardiovascular disease (CVD) in part due to their cancer treatment. Limited data are available on CVD risk among young breast cancer survivors. Methods: Women aged 30-40 years at diagnosis with stage 0-III breast cancer enrolled in a prospective cohort study of women diagnosed with breast cancer at ≤40 were eligible for inclusion in this analysis. Data were obtained from serial surveys and electronic medical records at breast cancer diagnosis and 5-year follow-up. We calculated “excess heart age,” which incorporates a CVD risk-based score (calculated using age, systolic blood pressure, blood pressure medication, diabetes, smoking, body mass index) to estimate the difference in years between an individual’s chronological age and their CVD-risk adjusted age. Multivariable logistic regression models (adjusting for age at diagnosis, stage, and race) were fitted to evaluate associations between treatment (radiation, endocrine therapy, anthracyclines, and trastuzumab) and having a change in excess heart age ≥2 years from baseline to 5 years. Results: Among 372 young breast cancer survivors, mean age at diagnosis was 36.6 (SD 2.89), 93% were white, and 79% were diagnosed with stage I or II breast cancer. Mean excess heart age was.32 (SD: 6.16) years at baseline, which declined to -.07 (SD 6.64) at 5-year follow-up (p=.17). At 5 years, 31% (n=114) of women experienced an increase of at least 2 years in their excess heart age since diagnosis, and their mean excess heart age was 4.34 years (range -9 to 30). In multivariable analyses, receipt of trastuzumab was associated with higher odds (OR: 1.68, 95% CI: 1.02-2.77) of experiencing an increase of ≥2 years in excess heart age between diagnosis and 5 years of follow-up. Endocrine therapy, anthracyclines, and radiation were not significantly associated with a change in excess heart age of ≥2 years at 5 years post-diagnosis. Conclusions: At 5 years post-diagnosis, approximately 1/3 of young breast cancer survivors experienced a change from baseline in their excess heart age of ≥2 years. Further research is warranted to confirm findings regarding trastuzumab and excess heart age, and potential effects on longer-term cardiac outcomes in this population. Extended follow-up of this cohort may further quantify CVD risk over time.[Table: see text]

BackgroundThe diagnosis and treatment of breast cancer can have profound effects on a young woman's family planning and fertility, particularly among women with hormone receptor–positive breast cancer.MethodsThe Young Women's Breast Cancer Study was a multicenter cohort of women aged 40 years or younger and newly diagnosed with breast cancer from 2006 to 2016. Surveys included assessments of fertility concerns, endocrine therapy (ET) preferences, and use. Characteristics were compared between women who reported that fertility concerns affected ET decisions and those who did not. Logistic regression was used to identify factors associated with having an ET decision affected by fertility concerns.ResultsOf 643 eligible women with hormone receptor–positive, stage I to III breast cancer, one‐third (213 of 643) indicated that fertility concerns affected ET decisions. In a multivariable analysis, only parity at diagnosis was significantly associated with fertility concerns affecting ET decisions (odds ratio for nulliparous vs ≥2 children, 6.96; 95% confidence interval, 4.09‐11.83; odds ratio for 1 vs ≥2 children, 5.30; 95% confidence interval, 3.03‐9.87). Noninitiation/nonpersistence was higher among women with fertility concerns versus those without fertility concerns (40% vs 20%; P < .0001). Among women with fertility‐related ET concerns, 7% (15 of 213) did not initiate ET, and 33% (70 of 213) were nonpersistent over 5 years of follow‐up. Of these women, 66% (56 of 85) reported 1 or more pregnancies or pregnancy attempts; 27% (15 of 56) had resumed ET at the last available follow‐up through 5 years.ConclusionsConcern about fertility is a contributor to adjuvant ET decisions among a substantial proportion of young breast cancer survivors. Ensuring family planning is addressed in the setting of ET recommendations should be a priority throughout the cancer care continuum.

Abstract Background: Young age at diagnosis is an independent risk factor for recurrence and death from breast cancer (BC), with the greatest impact of young age demonstrated in hormone receptor positive (HR+) disease. Younger women are less likely to be adherent to endocrine therapy (ET), which may contribute to disparate outcomes. Methods: As part of a prospective cohort that enrolled women with BC diagnosed at age ≤40 between 2006-2016, we identified women with HR+, Stage I-III BC. Serial surveys with items assessing socio-demographic and treatment information including medication use are administered 1-2 times per year. Medical record review was used to ascertain stage and HR status and to confirm recurrent disease (locoregional, distant, or new primary breast cancer). Women who initiated ET but discontinued it &lt;5-years post-diagnosis without resumption were classified as non-persistent. Univariable and multivariable regression models were fit to identify predictors of non-persistence and recurrence.Results: Among 607 women who initiated ET (median age at diagnosis: 36, range:17-40; 38%, 45%, 17% were Stage 1, 2, and 3, respectively).16% (99/607) were non-persistent, of whom 30% (30/99) discontinued ET ≤2 years post-diagnosis and over half had discontinued (54%, 54/99) by 3 years. In multivariable regression, those who were younger at diagnosis (age ≤30 vs. 36-40: OR: 3.39, 95% CI: 1.84-6.24; age 31-36 vs. 36-40: OR: 2.81 95% CI: 1.70-4.64) were more likely to discontinue ET while those with a higher stage at diagnosis were less likely to discontinue ET (Stage 2 vs. 1: OR: 0.46, 95% CI: 0.29-0.74; Stage 3 vs 1: OR: 0.32, 95% CI: 0.15-0.68). At a median follow-up time from diagnosis of 7.8 years (range 1-13 years), 15% of women (88/607) recurred or developed a new primary BC at a median time from diagnosis of 3.5 years (range 1-12 years). Of these, 66% (58/88) were distant recurrences, 32% (28/88) loco-regional, and 2% (2/88) new primary BCs. Rates of recurrence were higher among women who were persistent (81/508, 16%) vs. non-persistent (7/99, 7%, p=0.02). In multivariable regression, those who were non-persistent were less likely to recur (OR: 0.43, 95% CI: 0.19-0.98) while those with a higher stage were more likely to recur (Stage 3 vs. 1: OR: 2.36, 95% CI: 1.03-5.41). Sociodemographic, patient, and other treatment factors did not predict recurrence. Conclusions: Approximately 16% of young women with HR+ BC stop ET earlier than indicated, however non-persistence was not a risk factor for BC recurrence a median of 8 years following diagnosis in our cohort. Importantly, women with higher risk disease who are likely to benefit most from adherence to ET were less likely to discontinue treatment. Extended follow-up will further inform the impact of non-persistence on the incidence of late recurrences for which women with HR+ BC are at increased risk. Citation Format: Shoshana M Rosenberg, Yue Zheng, Philip Poorvu, Kathryn Ruddy, Rachel Gaither, Rulla Tamimi, Lidia Schapira, Jeffrey Peppercorn, Steven Come, Virginia Borges, Ann Partridge. Endocrine therapy non-persistence and recurrence in young women with early stage breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD2-08.