Ruddy, Kathryn J.

Abstract Purpose/Objectives: Proton therapy is under investigation in breast cancer as a strategy to reduce heart and lung exposure, which is associated with late cardiopulmonary adverse events and secondary malignancy. To date, studies investigating postmastectomy radiotherapy (PMRT) with protons have used conventional fractionation. We hypothesized that condensing treatment to 15 fractions would be safe based on evidence that breast cancer is more sensitive to higher dose fractions than surrounding normal tissues. Materials/Methods: We conducted a randomized non-inferiority phase II trial comparing conventional and hypofractionated proton PMRT with primary endpoint of 24-month complication rate (defined as grade 3 or higher late adverse events using CTCAE, v 4.0 and/or unplanned surgical intervention in patients undergoing mastectomy with reconstruction). With a 10% non-inferiority margin the study ensured 80% power and had a one sided-type I error rate of 0.05. Cardiotoxicity was assessed with serial transthoracic conventional and 2-dimensional speckle tracking echocardiography (2D-STE). Eligibility included age ≥ 18 years with non-inflammatory breast cancer resected by mastectomy with indications for PMRT. Assignment of treatments was balanced with respect to immediate breast reconstruction (IBR). Conventional fractionation group received 50 Gy in 25 fractions of 2 Gy, and hypofractionation group received 40.05 Gy in 15 fractions of 2.67 Gy (RBE 1.1). Target volume included the chest wall and axillary, supraclavicular, and internal mammary lymph nodes. All patients were treated with multi-field optimized pencil beam scanning (intensity modulated proton therapy). Results: Between 2016 and 2018, 82 patients were enrolled and randomized (41 conventional, 41 hypofractionation). Median patient age was 52 years. 32.9% were staged T3-T4 and 79.3% node positive at diagnosis. 57 of 82 patients (69.5%) elected IBR. The median mean heart dose was 0.49 Gy and the median ipsilateral lung volume receiving 40% of prescription or greater (V40%) was 13.6%. No significant changes on conventional or 2D-STE at end-of-treatment or 3-month follow-up compared to baseline were observed. The rate of ≥ grade 2 acute dermatitis was lower with hypofractionation (44% vs 15%, p = 0.006). Other ≥ grade 2 acute adverse events including esophagitis (0 vs 5%), infection (5% vs 2.4%) and skin hyperpigmentation (7.3% vs 4.8%) were not significantly different between the two arms. With a median follow-up of 38.3 months, the 24-month complication rate was conventional 14.6% vs hypofractionation 17.1% (absolute difference 2.4%, p=0.17, 95% CI [-, 15.7%]). In patients with IBR, 6 of 28 (21.4%) conventional and 7 of 29 (24.1%) hypofractionated patients developed complications (p =0.80). There was no significant difference in 3-year disease-free survival between the conventional (89.4%; 95% CI 80.0 – 99.8%) and hypofractionated (92.4%, 95% CI 84.5 – 100.0%) arms (p = 0.91). One local recurrence occurred in the hypofractionated arm simultaneous with regional and distant relapse. The remaining 6 recurrences were isolated distant events. Conclusions: Proton PMRT provided excellent locoregional control and normal tissue sparing. There were no subclinical echocardiographic changes indicative of radiation-induced cardiac dysfunction. Hypofractionation resulted in comparable disease control, tolerability and reconstruction outcomes as conventional fractionation. Although non-inferiority of hypofractionation could not be established based on the upper bound of the 95% confidence interval for complication rate being greater than 10%, both conventional and hypofractionation may be considered appropriate regimens for ongoing phase 3 randomized trials comparing photon and proton radiotherapy. Citation Format: Robert Mutter, Sharmila Giri, Briant Fruth, Nicholas Remmes, Aman Anand, Kathryn Ruddy, Hector Villarraga, Sebastian Santos Patarroyo, Elizabeth Yan, Kenneth Merrell, Lisa McGee, Tamara Vern-Gross, Bradley Stish, Robert Gao, Judy C. Boughey, Sean Park, Kimberly Corbin, Carlos Vargas. Phase II randomized trial of conventional versus hypofractionated post-mastectomy proton radiotherapy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS4-05.

Abstract Patients with hormone-receptor positive, early-stage breast cancer are at considerable risk for late recurrence. Previous randomized clinical trials have shown that extending adjuvant tamoxifen to ten vs. five years improves disease-free survival (and overall survival in one trial). Adding five years of an aromatase inhibitor (AI) after five years of tamoxifen has also been shown to significantly improve disease-free survival in postmenopausal patients. Benefit from extending adjuvant AI therapy beyond five years in patients who have received five years of an AI or tamoxifenàAI has also been recently demonstrated in several clinical trials but the absolute benefit appears small and the ideal duration of the extended therapy is still a topic of debate. Over the past decade, efforts have focused on identifying predictors of risk of late recurrence and predictors of benefit from extended endocrine therapy. Clinicopathologic factors and circulating tumor cells can predict risk of late recurrence but not benefit from extended ET. Several commercially available genomic classifiers can further stratify risk of late recurrence, and some have also been found to predict benefit from extended ET. Their clinical utility for tailoring the use of extended endocrine therapy continues to evolve. Citation Format: Eleftherios (Terry) Mamounas, Kathryn Ruddy. Duration of endocrine therapy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr CC1-2-1.

Background: The potential gonadotoxicity of anti-HER2 agents remains largely unknown, and limited, conflicting evidence exists for taxanes. Antimüllerian hormone (AMH) is an established biomarker of ovarian reserve that may aid in quantifying anticancer treatment–induced gonadotoxicity. Patients and Methods: The present biomarker analysis of the randomized phase III neoadjuvant NeoALTTO trial included premenopausal women aged ≤45 years at diagnosis of HER2-positive early breast cancer with available frozen serum samples at baseline (ie, before anticancer treatments), at week 2 (ie, the “biological window” of anti-HER2 therapy alone), and/or at the time of surgery (ie, after completing paclitaxel + anti-HER2 therapy, before starting adjuvant chemotherapy). Results: The present analysis included 130 patients with a median age of 38 years (interquartile ratio [IQR], age 33–42 years). AMH values at the 3 time points differed significantly (P<.001). At baseline, median AMH levels were 1.29 ng/mL (IQR, 0.56–2.62 ng/mL). At week 2, a small but significant reduction in AMH levels was observed (median, 1.10 ng/mL; IQR, 0.45–2.09 ng/mL; P<.001). At surgery, a larger significant decline in AMH levels was observed (median, 0.01 ng/mL; IQR, 0.01–0.03 ng/mL; P<.001). Although the type of anti-HER2 treatment (trastuzumab and/or lapatinib) did not seem to impact the results, age and pretreatment ovarian reserve had a major influence on treatment-induced gonadotoxicity risk. Conclusions: This NeoALTTO biomarker analysis showed that anti-HER2 therapies alone had limited gonadotoxicity but that the addition of weekly paclitaxel resulted in marked AMH decline with possible negative implications for subsequent ovarian function and fertility.

PURPOSE To estimate the risk of contralateral breast cancer (CBC) among women with germline pathogenic variants (PVs) in ATM, BRCA1, BRCA2, CHEK2, and PALB2. METHODS The study population included 15,104 prospectively followed women within the CARRIERS study treated with ipsilateral surgery for invasive breast cancer. The risk of CBC was estimated for PV carriers in each gene compared with women without PVs in a multivariate proportional hazard regression analysis accounting for the competing risk of death and adjusting for patient and tumor characteristics. The primary analyses focused on the overall cohort and on women from the general population. Secondary analyses examined associations by race/ethnicity, age at primary breast cancer diagnosis, menopausal status, and tumor estrogen receptor (ER) status. RESULTS Germline BRCA1, BRCA2, and CHEK2 PV carriers with breast cancer were at significantly elevated risk (hazard ratio > 1.9) of CBC, whereas only the PALB2 PV carriers with ER-negative breast cancer had elevated risks (hazard ratio, 2.9). By contrast, ATM PV carriers did not have significantly increased CBC risks. African American PV carriers had similarly elevated risks of CBC as non-Hispanic White PV carriers. Among premenopausal women, the 10-year cumulative incidence of CBC was estimated to be 33% for BRCA1, 27% for BRCA2, and 13% for CHEK2 PV carriers with breast cancer and 35% for PALB2 PV carriers with ER-negative breast cancer. The 10-year cumulative incidence of CBC among postmenopausal PV carriers was 12% for BRCA1, 9% for BRCA2, and 4% for CHEK2. CONCLUSION Women diagnosed with breast cancer and known to carry germline PVs in BRCA1, BRCA2, CHEK2, or PALB2 are at substantially increased risk of CBC and may benefit from enhanced surveillance and risk reduction strategies.

AbstractBackgroundThe relationship between CINV duration and recurrence in subsequent cycles is largely unstudied. Our objective was to determine if patients experiencing CINV in their first cycle of chemotherapy (C1) would face increased risk of CINV in later cycles and whether the duration of the CINV would predict increased risk of recurrence.Patients and MethodsUsing data from a previously reported phase III trial, we assessed patients’ recurrence of breakthrough CINV after antiemetic prophylaxis for anthracycline+cyclophosphamide (AC) for breast cancer, comparing C1 short CINV vs. extended CINV as a secondary analysis. Complete response (CR) and CINV duration were primary and secondary endpoints, respectively. CR was considered prophylaxis success; lack of CR was considered treatment failure (TF).ResultsAmong 402 female patients, 99 (24.6%) had TF in C1 (TF1). The remaining 303 patients (CR1) had ≥93% CR rates in each subsequent cycle, while the 99 patients with TF1 had TF rates of 49.8% for cycles 2-4 (P &lt; .001). The 51 patients with extended TF (≥3 days) in C1 had recurrent TF in 73/105 later cycles (69.5%, P &lt; .001), while the 48 patients with short TF (1-2 days) in C1 had recurrent TF in 33/108 later cycles (30.6%). The relative risk of recurrence after C1 extended TF was 2.28 (CI 1.67-3.11; P &lt; .001) compared to short TF.ConclusionsProphylaxis success in C1 led to &gt;90% repeat success across cycles of AC-based chemotherapy. For patients with breakthrough CINV, extended duration strongly predicted recurrent CINV. The duration of CINV should be closely monitored, and augmenting antiemetic prophylaxis considered for future cycles when extended CINV occurs.

Objective: We sought to evaluate local/regional recurrence rates after breast-conserving surgery in a cohort of patients enrolled in legacy trials of the Alliance for Clinical Trials in Oncology and to evaluate variation in recurrence rates by receptor subtype. Background: Multiple randomized controlled trials have demonstrated equivalent survival between breast conservation and mastectomy, albeit with higher local/regional recurrence rates after breast conservation. However, absolute rates of local/regional recurrence have been declining with multi-modality treatment. Methods: Data from 5 Alliance for Clinical Trials in Oncology legacy trials that enrolled women diagnosed with breast cancer between 1997 and 2010 were included. Women who underwent breast-conserving surgery and standard systemic therapies (n=4,404) were included. Five-year rates of local/regional recurrence were estimated from Kaplan-Meier curves. Patients were censored at the time of distant recurrence (if recorded as the first recurrence), death, or last follow-up. Multivariable Cox proportional hazards models were used to identify factors associated with time to local/regional recurrence, including patient age, tumor size, lymph node status, and receptor subtype. Results: Overall 5-year recurrence was 4.6% (95% CI=4.0-5.4%). Five-year recurrence rates were lowest in those with ER+ or PR+ tumors (Her2+ 3.4% [95% CI 2.0-5.7%], Her2- 4.0% [95% CI 3.2-4.9%]) and highest in the triple-negative subtype (7.1% [95% CI 5.4-9.3%]). On multivariable analysis, increasing nodal involvement and triple-negative subtype were positively associated with recurrence (P<0.0001). Conclusions: Rates of local/regional recurrence after breast conservation in women with breast cancer enrolled in legacy trials of the Alliance for Clinical Trials in Oncology are significantly lower than historic estimates. This data can better inform patient discussions and surgical decision-making.

Abstract Background: Young women with DCIS are at increased risk of recurrence and second BC compared to older women and may derive the greatest benefit from risk reduction strategies. Little is known about treatment decision-making, engagement in preventive behaviors, or fear of recurrence among young DCIS survivors. Thus, we sought to investigate treatment and prevention issues in this population. Methods: Using a multicenter prospective cohort that enrolled 1302 women with stage 0-IV BC at age ≤40, we identified participants with DCIS only who completed surveys in the year following diagnosis (dx). Surveys assessed treatment decisions, lifestyle factors (alcohol, smoking, physical activity [PA]), and fear of recurrence (Lasry Scale). Data was summarized with descriptive statistics and groups were compared with Fisher’s exact test. Results: Among 87 patients (median age 38, range 26-40), 75 had available treatment decision data, 19 (25%) of whom had breast-conserving surgery (BCS), 11 (15%) unilateral mastectomy (UM), and 45 (60%) bilateral mastectomy (BM). Most (77%) indicated their doctor said BCS was an option or recommended, including 34 (59%) who had BM. Of 40 patients who reported a patient-driven surgical decision, 73% had BM, 13% UM, and 15% BCS. Among 15 patients who reported the decision as doctor-driven, none had BM, 27% UM, and 73% BCS. Those who had BM were more likely to be extremely confident about the decision (80% vs. 73% UM vs. 53% BCS, p=0.022). Adjuvant tamoxifen was used by 10/27 (37%) patients with ER+ DCIS who had BCS/UM. Most who took tamoxifen reported this decision was shared with their doctor (90%); 1 reported the decision was made on her own. Of the 17 patients who did not take tamoxifen, 88% indicated their doctor said endocrine therapy was an option or recommended. Among all 87 patients, 31 (36%) were former and 3 (4%) were current smokers at baseline assessment (median 5 months post-dx); 51 (59%) never smoked. Overall, 4 quit within 1 year of dx. Most patients (83%) were current drinkers at baseline, though 79% consumed &lt;5 alcoholic beverages/week; 8% reported lower consumption at 1 year. Regarding PA at 1 year, 73% (58/80) reported ≥150 minutes of moderate-intensity PA/week. Overall, 41% of young survivors were at least moderately concerned about their BC coming back, with concern varying numerically by surgery (65% post-BCS, 50% post-UM, 29% post-BM, p=0.053). Conclusions: BC recurrence concerns were frequent among young DCIS patients, particularly among those with remaining breast tissue. BM decisions were largely patient-driven and made with high confidence, reflecting preferences towards surgical prevention. While adherence to survivorship lifestyle guidelines was high, including not smoking, consumption of ≤7 drinks/week, and engaging in PA, tamoxifen use was low, even when offered by a provider. Young DCIS survivors appear motivated to lower future BC risk through surgery and maintenance of healthy behaviors, and less so with tamoxifen; such values should be considered during treatment and survivorship counseling. Citation Format: Megan E. Tesch, Julia S. Wong, Laura Dominici, Kathryn J. Ruddy, Rulla Tamini, Lidia Schapira, Virginia F. Borges, Ellen Warner, Steven E. Come, Karen Sepucha, Laura C. Collins, Ann H. Partridge, Shoshana M. Rosenberg. Breast cancer (BC) risk reduction in young women with ductal carcinoma in situ (DCIS) [abstract]. In: Proceedings of the AACR Special Conference on Rethinking DCIS: An Opportunity for Prevention?; 2022 Sep 8-11; Philadelphia, PA. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_1): Abstract nr PR009.

Abstract Introduction: The relationship between germline pathogenic variants (PVs) in cancer predisposition genes and ductal carcinoma in situ (DCIS) is not well established. The objective of this study is to determine the risks of DCIS and contralateral breast cancer among women with DCIS associated with germline PVs in cancer predisposition genes. Methods: Associations between pathogenic variants in 11 cancer predisposition genes (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, MSH6, PALB2, RAD51C, and RAD51D) and DCIS were determined in case control analyses of a population-based cohort of 3876 women with DCIS and age-matched unaffected women, and in a clinical cohort of 9887 DCIS cases undergoing clinical genetic testing at Ambry Genetics and unaffected reference controls. The incidence of contralateral breast cancer risk in BRCA1, BRCA2, and PALB2 PV carriers with DCIS was also evaluated in a time-to-event analysis. Results: The mean age at diagnosis of DCIS was 50 years in the clinical testing cohort and 59 years in the population-based cohort. The frequency of PVs in 11 predisposition genes among DCIS cases was 6.9% in the clinical testing cohort and 4.9% in the population-based cohort. PVs in ATM, BRCA1, BRCA2, CHEK2, MSH6, PALB2, and RAD51D were associated with significantly increased risks (Odds Ratio (OR) &gt;2) of DCIS in the clinical testing cohort whereas only PVs in BRCA1, CHEK2, PALB2, and ATM were associated with significantly increased risks of DCIS in the population-based cohort. The cumulative incidence of contralateral breast cancer among BRCA1, BRCA2, and PALB2 PV carriers with DCIS was 11% in 5-years and 20% in 15-years. Conclusions: This study provides new insights into PVs that predispose to DCIS. In addition, it establishes an increased risk of contralateral breast cancer risk among women with DCIS who are carriers of PVs in BRCA1, BRCA2, or PALB2. These findings will guide surveillance and risk reducing strategies in germline PV carriers with DCIS. Citation Format: Huaizhi Huang, Ronan E. Couch, Holly LaDuca, Siddhartha Yadav, Eric C. Polley, Nicholas J. Boddicker, Jie Na, Rohan D. Gnanaolivu, David E. Goldgar, Tina Pesaran, Steven N. Hart, Jill S. Dolinsky, Julie R. Palmer, Lauren Teras, Alpa V. Patel, Kathryn J. Ruddy, Janet E. Olson, Celine M. Vachon, Peter Kraft, Song Yao, Amy Trentham-Dietz, Katherine L. Nathanson, Jeffrey N. Weitzel, Susan M. Domchek, Fergus J. Couch, Chunling Hu. Risks of ductal carcinoma in situ of the breast associated with pathogenic variants in cancer predisposition genes [abstract]. In: Proceedings of the AACR Special Conference on Rethinking DCIS: An Opportunity for Prevention?; 2022 Sep 8-11; Philadelphia, PA. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_1): Abstract nr A003.

Abstract We previously described the hypotheses, outcomes, design, and analysis for E2C2, a pragmatic stepped-wedge trial to assess an intervention to improve symptom control in patients with cancer. Subsequent consideration of the design and cohort led to the addition of a second primary hypothesis. This article describes and presents the rationale for this second hypothesis. This addendum also details a revised analytic approach, necessitated by inconsistencies in the original analytic plan. The design, outcomes, and other aspects of the protocol remain unchanged.

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.