Breast Cancer Recurrence-free Interval Research Articles

Abstract GS02-07: Loco-Regional Irradiation in Patients with Biopsy-proven Axillary Node Involvement at Presentation Who Become Pathologically Node-negative After Neoadjuvant Chemotherapy: Primary Outcomes of NRG Oncology/NSABP B-51/RTOG 1304

Abstract Background: The benefit of adjuvant regional nodal irradiation including the chest wall after mastectomy (CWI+RNI) and with whole breast irradiation (WBI+RNI) after breast conserving surgery (BCS) is well established in pts with pathologically positive axillary nodes (pN+). Pts who present with axillary node involvement (cN+), receive neoadjuvant chemotherapy (NC), and are found to be pathologically node-negative at surgery (ypN0), have lower loco-regional recurrence (LRR) rates compared to those who remain pathologically node-positive (ypN+). This phase III, randomized trial aimed to evaluate whether CWI+RNI after mastectomy or addition of RNI to WBI after BCS significantly improves invasive breast cancer recurrence-free interval (IBC-RFI) in cN+ pts found to be ypN0 after NC. Methods: Eligible pts had clinical cT1-3, N1, M0 invasive breast cancer (biopsy-proven N+ by FNA/core needle bx), completed ≥8 wks of NC (and anti-HER2 therapy if HER2+), and were ypN0 after mastectomy or BCS and sentinel node biopsy (SLNB, ≥2 nodes), axillary lymph node dissection (ALND), or both. Pts were randomized to “No RNI” (i.e., observation after mastectomy or WBI after BCS) vs. “RNI” (i.e., CWI+RNI after mastectomy or WBI+RNI after BCS). Primary endpoint was IBC-RFI. Secondary endpoints reported here: LRR-free interval (LRRFI), distant recurrence-free interval (DRFI), disease-free survival (DFS), and overall survival (OS). Study was designed to have 80% power to detect 35% reduction in annual rate of IBC-RFI for an absolute risk reduction of 4.6% (5-yr cumulative rate). Per protocol, final analysis was to occur after 172 events or 10 yrs after study initiation.Here we report the time-driven analysis prespecified in the protocol. Results: From 9/13-12/20, 1,641 pts were enrolled; 1,556 pts were available for primary event analysis; median f/u time 59.5 mos (IQR 40.7-74.1). Pt/tumor characteristics were well balanced between groups. Median age 52 yrs (range 21-84); 31% non-white; 21% cT1, 60% cT2, 19% cT3; 23% triple-negative, 21% HR+/HER2-, 56% HER2+; 58% BCS; 55% SLNB, 45% ALND+/-SLNB; and 78% had breast pathologic complete response. At the time of the analysis, 109 IBC-RFI events (63% of the planned 172) were confirmed (“No RNI”: 59, “RNI”: 50). There was no statistically significant difference between groups for IBC-RFI (HR=0.88, 95%CI 0.60-1.29; p=0.51), 5-yr point estimates: 91.8% for “No RNI” and 92.7% for “RNI.” There were no statistically significant differences between the treatment groups for secondary endpoints. There were no study-related deaths and no unexpected toxicities.Grade 4 toxicity was rare (0.1% with “No RNI”, 0.5% with “RNI”); 6.5% of pts developed grade 3 toxicity in “No RNI” and 10% in “RNI” group. Most common grade 3 toxicity was radiation dermatitis (3.3% in “No RNI,” 5.7% in “RNI”). Conclusion: In pts who present with biopsy-proven axillary node involvement and convert their axillary nodes to ypN0 after NC, CWI+RNI after mastectomy, or WBI+RNI after BCS, did not significantly improve IBC-RFI, LRRFI, DRFI, DFS, or OS. These findings suggest that downstaging involved axillary nodes with NC can result in optimization of adjuvant radiotherapy without adversely affecting oncologic outcomes. Follow-up of pts for long-term outcomes continues. NCT01872975 *EPM and JW are co-first authors. Table 1 Citation Format: Eleftherios Mamounas, Hanna Bandos, Julia White, Thomas Julian, Atif Khan, Simona Shaitelman, Mylin Torres, Frank Vicini, Patricia Ganz, Susan McCloskey, Nilendu Gupta, X. Allen Li, Peter Lucas, Nadeem Abu-Rustum, Saumil Gandhi, Rahul Tendulkar, Robert Coleman, Keiichi Fujiwara, Samantha Seaward, William Irvin, Kristin Higgins, Robert Mutter, Jean-Francois Boileau, Andrew Muskovitz, Reshma Jagsi, Anna Weiss, Curran Walter Jr., Norman Wolmark. Loco-Regional Irradiation in Patients with Biopsy-proven Axillary Node Involvement at Presentation Who Become Pathologically Node-negative After Neoadjuvant Chemotherapy: Primary Outcomes of NRG Oncology/NSABP B-51/RTOG 1304 [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr GS02-07.

Abstract P4-07-36: Chest-Wall and Nodal Irradiation in Non-Metastatic, Node Positive Breast Cancer Patients with Pathologic Complete Response After Neoadjuvant Chemotherapy and Surgery, in A Retrospective Cohort of Women Aged 45 Years and Younger

Abstract Purpose/Objective(s): Several randomized clinical trials and non-randomized studies have consistently shown that achievement of pathologic complete response (pCR) in the breast with negative axillary nodes is associated with excellent long-term outcomes. NSABP B-511 is a phase III trial aimed to determine if chest wall and regional nodal irradiation (CWRNI) post-op reduces invasive breast cancer recurrence-free interval in patients (pts) with positive axillary lymph nodes (LN) who achieve pCR after neoadjuvant chemotherapy (NAC). However, physicians might be biased towards avoiding enrollment of young patients (≤ 45 years) in this trial. Which in turn, could give way to this population becoming under-represented at the time of determining the standard of care. Our primary objective is to determine if the omission of CWRNI is associated with an increased risk of recurrence in a young patient population. Materials/Methods: Data were obtained from two institutions in South Florida. Patients aged ≤ 45 years, with non-metastatic invasive breast cancer, and positive clinical (LN) involvement, diagnosed between 2010 to 2017 and treated with NAC were identified through retrospective chart review. Disease recurrence including local and distant recurrence data were collected. The Kaplan-Meier survival function was used for plotting patients treated with CWRNI vs no CWRNI and the log-rank test was used to evaluate the recurrence-free survival according to groups. We reported recurrence probabilities at 5 years. Additionally, we also estimated hazard ratios (HRs) of patients treated with CWRNI vs no CWRNI using Cox proportional hazards regression analysis. Results: A total of 154 patients were identified. Median age was 39 years (24-45). Patients were 57% ER+, 33% HER2+, 29% triple negative and 59.1% were stage 3, with only 1 male patient in the cohort. PCR was achieved in 22.1% (34/154) of pts, and CWRNI frequency in these patients was 81.3%. Overall, 79.9% of pts received post-op CWRNI. Recurrence frequency in patients with a pCR who received CWRNI was 4/26 vs 2/6 in pts that did not receive CWRNI. The Kaplan-Meier survival curves indicated an overall probability of recurrence at 5 years of 31.9% (95%CI 3.8% – 51.8%) in patients that did not receive CWRNI vs 27.49% (95%CI 18.42% – 35.56%) in patients that received CWRNI (log rank p=0.55) however, statistical significance was not met. Cox regression indicated that omission of CWRNI was not associated with an increased risk of recurrence (HR 1.3, 95%CI 0.54 – 3.11, p=0.55). In patients that had a pCR after NAC, omission of CWRNI was not associated with an increased risk of recurrence (HR 2.004, 95%CI 0.36 – 10.9, p=0.42). However, the sample size for these analyses was too small to achieve significance. Conclusion: This data highlights the tendency of giving CWRNI to younger patients with clinically node-positive disease at diagnosis regardless of response to NAC. Overall, absolute recurrence in this cohort was very low. Although an absolute number of recurrences favored CWRNI in the setting of pCR, this was not statically significant given the small sample size. Citation Format: Danielle Cerbon, Alex Sanchez-Covarrubias, Brianna Conte, Cristiane Takita, Lora Freedman, Jessica Meshman, Stuart Samuels, Caroline Shermoen, Neha Goel, Ruben Carmona, Lora Wang. Chest-Wall and Nodal Irradiation in Non-Metastatic, Node Positive Breast Cancer Patients with Pathologic Complete Response After Neoadjuvant Chemotherapy and Surgery, in A Retrospective Cohort of Women Aged 45 Years and Younger. [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 P4-07-36.

Association Between Regional Nodal Irradiation and Breast Cancer Recurrence-Free Interval for Patients With Low-Risk, Node-Positive Breast Cancer

Randomized clinical trials have shown that regional nodal irradiation (RNI) in patients with unselected N1 breast cancer improves breast cancer-specific survival. However, the benefit of RNI in women with biologically low-risk N1 breast cancer is uncertain. We conducted a population-based study to determine whether RNI is associated with improved breast cancer recurrence-free interval (BCRFI) in this population. Patients aged 40 to 79 years with pT1-2 pN1 (node-positive) breast cancer diagnosed between 2005 and 2014 were identified. The inclusion criteria were modeled off of the TAILOR RT study, which is a randomized noninferiority clinical trial designed to assess the value of RNI in patients with low-risk N1 disease. Eligible patients had breast-conserving surgery or mastectomy and axillary lymph node dissection with 1 to 3 positive nodes, breast-conserving surgery and sentinel lymph node biopsy with 1 to 2 positive nodes, or mastectomy and sentinel lymph node biopsy with 1 positive node. Additionally, patients had luminal A breast cancers, as approximated by estrogen receptor positive (Allred 6-8/8), progesterone receptor (PR) positive (Allred 6-8/8), human epidermal growth factor receptor 2-negative, and grade 1 to 2 immunohistochemical testing. All patients were prescribed hormonal treatment. The primary endpoint of BCRFI, the time to any breast cancer recurrence or breast cancer-related death, was analyzed using a multivariate competing risks analysis. The cohort included 1169 women with a median follow-up of 9.2 years. Radiation treatments were not performed in 151 women treated with mastectomy alone, were delivered to the breast only in 133 women, and were delivered locoregionally in 885 women. Patients undergoing RNI were younger (median age: 58 vs 62 years), more likely to have 2 to 3 macroscopic lymph nodes involved, and more often received chemotherapy (all P < .05). The 10-year estimate of BCRFI was 90% without RNI versus 90% with RNI (P=.5). On multivariable analysis, RNI was not a significant predictor of BCRFI (hazard ratio: 1.0; P=.9). In this retrospective analysis, RNI was not associated with improved BCRFI for women with biologically low-risk N1 breast cancer. We advocate accrual to the ongoing TAILOR RT study.

Regional Nodal Irradiation for Low-Risk, Node-Positive Breast Cancer

The benefit of regional nodal irradiation (RNI) for node-positive, low-risk breast cancer is controversial. The ongoing TAILOR RT trial is enrolling breast cancer patients with 1-3 involved macroscopic nodes and a low risk Oncotype DX Recurrence Score (< 18) to determine the breast cancer recurrence-free interval (BCRFI) with and without RNI. The objective of this study was to determine if RNI was associated with improved BCRFI in a population of patients similar to those enrolling on TAILOR RT.We interrogated a population-based database, which included all women treated for breast cancer in the province. Inclusion criteria were: age 40-79, pT1-2 pN1 (macroscopically node-positive) breast cancer, and diagnosis between 2005 and 2014. To reproduce the inclusion criteria of TAILOR RT, patients could have had breast-conserving surgery (BCS) or mastectomy & axillary lymph node dissection (ALND) with 1-3 positive nodes, BCS & sentinel lymph node biopsy (SLNB) with 1-2 positive nodes or mastectomy & SLNB with 1 positive node. To select a cohort of patients likely to have Recurrence Score < 18, we only included Luminal A breast cancers. Luminal A was approximated based on the tumor being: ER positive (Allred 6-8/8), PR positive (Allred 6-8/8), HER2-negative, and Grade 1-2. All patients were started on hormonal treatment. The primary endpoint of BCRFI, which was the time to any breast cancer recurrence or breast cancer-related death, was analyzed using multivariate competing risks analysis. Secondary outcomes of locoregional recurrence and distant metastasis were analyzed with multivariate competing risks models, and overall survival was analyzed with multivariate cox analysis.We identified 1,169 eligible women. Median follow-up was 9.2 years. There were 885 patients who received RNI and 284 who did not undergo RNI. The RNI group was younger (median 62 versus 58 years), had a higher rate of nodal involvement, and were more likely to have received chemotherapy (all P < 0.05). The 10-year estimate of BCRFI was 90% in the no-RNI group versus 90% in the RNI group (P = 0.5). On multivariable analysis, RNI was not a significant predictor of BCRFI (HR = 1.0, P = 0.9). At 10-years, locoregional recurrence was 3.3% in the no-RNI group and 1.7% in the RNI group (P = 0.2). Distant metastasis at 10-years was 7.0% for the no-RNI group versus 8.8% for the RNI group (P = 0.5). Finally, overall survival at 10-years was 85% for the no-RNI group and 85% for the RNI group (P = 0.2). All secondary outcomes were analyzed in multivariate models, and, in all cases, RNI receipt was not associated with improved outcomes (all P > 0.05).RNI was not associated with improved outcomes in node-positive, low-risk breast cancers. This work underscores the importance of continued accrual onto the ongoing non-inferiority trial of RNI, TAILOR RT.

Abstract OT1-04-01: Adjuvant ovarian suppression plus aromatase inhibitor or tamoxifen for hormone receptor-positive breast cancer in women younger than 35 (ASPAIT): A multicenter randomized clinical trial

Abstract In SOFT study, subgroup analysis for hormone receptor-positive (HR+) breast cancer women younger than 35 years indicated better 5-year DFS in OFS+exemestane arm than OFS+tamoxifen. Since only about 11% of women included were younger than 35 years of age, this subgroup analysis result is underpowered. In addition, there still no specific randomized clinical trial focusing on endocrine treatment in women younger than 35 years of age. The purpose of this study is to compare the efficacy of gonadotropin releasing hormone agonists (GnRHa)+tamoxifen versus GnRHa+AIs in HR+ early breast cancer patients under age 35 with intermediate or high risk for disease recurrence. Study design This is a prospective, open label, multicentre, randomized controlled trial that compared the efficacy of GnRHa+tamoxifen versus GnRHa+AIs in HR+ early breast cancer patients under age 35 with intermediate or high risk for disease recurrence. This study was initiated by the first affiliated hospital of Sun Yat-sen university in 2016. Twenty-four hospitals in China participate in this trial. The protocol was approved by the appropriate regulatory and ethics authorities for each centre. This trial has been registrated at ClinicalTrials.gov. The NCT Number is NCT02914158. Criteria for patient eligibility: 1. Written informed consent must be signed. 2. ECOG≤2. 3. Histologically proven HR+ (ER≥1% by IHC) invasive breast cancer. 4. Age≤35, premenopausal. 5. No distant metastatic disease. 6. T≥2cm or with at least 1 axillary lymph node involved. 7. Patient must accept proper surgery, systemic therapy and radiation therapy if necessary. 8. Laboratory exam criteria for enrollment: hemoglobin ≥10g/dl, white blood cell ≥4,000/mm3, platelets ≥100,000/mm3, glutamic oxalacetic transaminase, glutamic-pyruvic transaminase, alkaline phosphatase ≤2 times upper limit of normal (ULN), total bilirubin, creatinine clearance rate ≤1.5 times ULN. Criteria for patient ineligibility: 1. Patients who are pregnant or lactating at the time of randomization or refuse to contraception.2. Patients who received organ transplantation. 3. Patients who have other malignant diseases within 5 years. 4. Patients with psychiatric disorder, peripheral or central nerve system disease or any disorder, which compromises ability to give informed consent or participate in this study. 5. Patients with sever hepatic, renal, cardiovascular, respiratory, digestive diseases or uncontrolled diabetes. 6. Patients who participate in other clinical trials. 7. Patients who allergy to goserelin, leuprorelin, tamoxifen or AIs. Statistical analysis According to previous results, 5-year DFS for OFS+tamoxifen in HR+ breast cancer patients under age 35 with intermediate or high risk of disease recurrence was 73% vs. 81% for OFS+AIs. This trial designed 80% power to detect a between-group difference using a two-sample log-rank test (two-sided a=0.05). To allow for missing 10% data, the study planned to enroll 680 patients (340 patients for each group) in 5 years. The statistical design assumed that 197 primary end point events should occur during 5-year follow-up and OFS+AIs should decrease 30% DFS relative risk. The calculations were performed using PASS 11. Treatment details Patients enrolled are randomized 1:1 to two arms in 8 weeeks after surgery, adjuvant chemotherapy or radiation therapy. Goserelin 3.6mg or leuprorelin 3.75mg is injected subcutaneously every 28 days for 5 years. Arm A: Tamoxifen 20mg orally daily. Arm B: Exemestane 25mg, letrozole 2.5mg or anastrozole 1mg orally daily. Stratification Stratified by HER2 and axillary lymph node status. Primary end point: Disease free survival. Secondary end point: Overall survival. Invasive Breast Cancer Recurrence-Free Interval. Adverse Effects Rate. Citation Format: Zhen Shan, Nan Shao, Zhongyu yuan, Qianjun Chen, Anqin Zhang, Kun Wang, Ailing Zhang, Li Cai, Yuhua Song, Herui Yao, Hongmin Ma, Heng Huang, Jianwen Li, Yuanqi Zhang, Lehong Zhang, Jincai Zhong, Hui Liu, Zhiyong Wu, Li Zhao, Feihai Ling, Weixiong Yang, Rui Zhuo, Xiangyang Song, Ying Lin. Adjuvant ovarian suppression plus aromatase inhibitor or tamoxifen for hormone receptor-positive breast cancer in women younger than 35 (ASPAIT): A multicenter randomized clinical trial [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT1-04-01.

Cctg MA.39 tailor RT: A randomized trial of regional radiotherapy in biomarker low-risk node-positive breast cancer (NCT03488693).

TPS602 Background: Biomarker low risk, ER positive (+), HER2 negative (-) breast cancer with low burden nodal involvement may be associated with good outcomes (Woodward 2016, Mamounas 2017). There is conflicting data regarding the efficacy of regional radiotherapy after breast conserving surgery (BCS) or mastectomy in these patients (Kyndi 2008, Whelan 2015, Poortmans 2015, Liu 2015). Our hypothesis is that the risk of recurrence in patients with biomarker low risk, ER+, Her2- breast cancer and involvement of 1-3 lymph nodes where regional RT is omitted will not be inferior to the risk of recurrence in patients treated with regional RT. Methods: MA39 is a Canadian Cancer Trials Group led, NCTN sponsored, randomized phase III study comparing breast cancer recurrence free interval (BCRFI) in patients with ER+, Her2-, LN 1-3+ breast cancer that is low risk as defined by Oncotype Dx Recurrence Score &lt; 18. Secondary objectives include a comparison of DFS, breast cancer mortality, OS, locoregional and distant recurrence free intervals, toxicity, arm volume and mobility measurements, patient reported outcomes and cost effectiveness. Key eligibility criteria include: age ≥ 40 years; BCS or mastectomy with axillary dissection and 1-3 positive axillary nodes; BCS and SLNB alone and 1-2 positive axillary nodes; mastectomy and SLNB alone and only 1 positive axillary node; planned endocrine therapy ≥ 5 years; adjuvant chemotherapy allowed. Statistical design: The primary analysis will be a test of non-inferiority (NI) in the intention to treat population. If the upper bound of a one-sided 95% interval for the hazard ratio for BCRFI is &lt; 1.4, NI will be declared. Using a one-sided α of 0.05 and a power of 87%, it is anticipated that 278 events are required. With an expected 5 years of accrual and 4.5 years of follow-up, 2140 patients are needed for the final sample size. Conduct to Date: Study activation May 30 2018. Participation as of February 2019: Registrations 64 Randomizations 26. CIRB approval for continuation of MA.39 was received on January 11 2019. Clinical trial information: NCT03488693.

NRG Oncology/NSABP B-51/RTOG 1304: Phase III trial to determine if chest wall and regional nodal radiotherapy (CWRNRT) post mastectomy (Mx) or the addition of RNRT to whole breast RT post breast-conserving surgery (BCS) reduces invasive breast cancer recurrence-free interval (IBCR-FI) in patients (pts) with pathologically positive axillary (PPAx) nodes who are ypN0 after neoadjuvant chemotherapy (NC).

TPS600 Background: This phase III post-NC trial evaluates if CWRNRT post-Mx or whole breast irradiation (WBI) with RNRT after BCS significantly reduces the IBCR-FI rate in pts with PPAx nodes that are pathologically negative after NC. Secondary aims are OS, LRR-FI, DR-FI, DFS-DCIS, second primary cancer, and comparison of RT effect on cosmesis in reconstructed Mx pts. Correlative science examines RT effect by tumor subtype, molecular outcome predictors for residual disease, and predictors for the degree of reduction in loco-regional recurrence. Methods: Clinical T1-3, N1 IBC PPAx nodes (FNA or core needle biopsy) pts complete ≥8 weeks of NC (anthracycline and/or taxane). HER2+ pts receive anti-HER2 therapy. Following NC, BCS or Mx, sentinel node biopsy (≥2 nodes) and/or Ax dissection with histologically negative nodes is performed. ER/PR and HER-2neu status before NC is required. Pts may receive appropriate adjuvant systemic therapy. Radiation credentialing with a facility questionnaire/case benchmark is required. Random assignment for Mx pts is to no CWRNRT or CWRNRT and for BCS pts to WBI or WBI+RNRT. Statistics: 1,636 pts are to be enrolled over 5 yrs (definitive analysis at 7.5 yrs). Study is powered at 80% to test that RT reduces the annual hazard rate of events for IBCR-FI by 35% for an absolute risk reduction of 4.6% (5-yr cumulative rate). Intent-to-treat analysis with 3 interim analyses (43, 86, and 129 events) and a 4th/final analysis at 172 events. Pt-reported outcomes focusing on RT effect will be provided by 736 pts before random assignment and at 3, 6, 12, and 24 mos. Accrual as of 2-7-19 is 1,164 (71.1%). Contacts: Protocol: CTSU member website https://www.ctsu.org . Questions: NRG Oncology Pgh Clin Coord Dpt: 1-800-477-7227 or ccd@nsabp.org . Pt entry: OPEN at https://open.ctsu.org or the OPEN tab on CTSU member website. Support: U10 CA-2166; -180868, -180822; 189867; Elekta NCT01872975 Clinical trial information: NCT01872975.

Abstract OT2-04-01: Phase III trial to determine if chest wall and regional nodal radiotherapy (CWRNRT) post mastectomy (Mx) or the addition of RNRT to whole breast RT post breast-conserving surgery (BCS) reduces invasive breast cancer recurrence-free interval (IBCR-FI) in patients (pts) with pathologically positive axillary (PPAx) nodes who are ypN0 after neoadjuvant chemotherapy (NC): NRG Oncology/NSABP B-51/RTOG 1304

Abstract This phase III post-NC trial evaluates if CWRNRT post-Mx or whole breast irradiation (WBI) with RNRT after BCS significantly reduces the IBCR-FI rate in pts with PPAx nodes that are pathologically negative after NC. Secondary aims are OS, LRR-FI, DR-FI, DFS-DCIS, second primary cancer, and comparison of RT effect on cosmesis in reconstructed Mx pts. Correlative science examines RT effect by tumor subtype, molecular outcome predictors for residual disease, and predictors for the degree of reduction in loco-regional recurrence. Methods: Clinical T1-3, N1 IBC PPAx nodes (FNA or core needle biopsy) pts complete ≥8 weeks of NC (anthracycline and/or taxane). HER2+ pts receive anti-HER2 therapy. Following NC, BCS or Mx, sentinel node biopsy (≥2 nodes) and/or Ax dissection with histologically negative nodes is performed. ER/PR and HER-2neu status before NC is required. Pts may receive appropriate adjuvant systemic therapy. Radiation credentialing with a facility questionnaire/case benchmark is required. Random assignment for Mx pts is to no CWRNRT or CWRNRT and for BCS pts to WBI or WBI+RNRT. Statistics: 1,636 pts are to be enrolled over 5 yrs (definitive analysis at 7.5 yrs). Study is powered at 80% to test that RT reduces the annual hazard rate of events for IBCR-FI by 35% for an absolute risk reduction of 4.6% (5-yr cumulative rate). Intent-to-treat analysis with 3 interim analyses (43, 86, and 129 events) and a 4th/final analysis at 172 events. Pt-reported outcomes focusing on RT effect will be provided by 736 pts before random assignment and at 3, 6, 12, and 24 mos. Accrual as of 6-21-18 is 967 (59.11%). Contacts: Protocol: CTSU member website https://www.ctsu.org. Questions: NRG Oncology Pgh Clin Coord Dpt: 1-800-477-7227 or ccd@nsabp.org. Pt entry: OPEN at https://open.ctsu.org or the OPEN tab on CTSU member website. NCT01872975 Support: U10 CA-2166; -180868, -180822; 189867; Elekta Citation Format: Mamounas EP, Bandos H, White JR, Julian TB, Khan AJ, Shaitelman SF, Torres MA, Vicini FA, Ganz PA, McCloskey SA, Paik S, Gupta N, Li XA, DiCostanzo DJ, Curran WJ, Wolmark N. Phase III trial to determine if chest wall and regional nodal radiotherapy (CWRNRT) post mastectomy (Mx) or the addition of RNRT to whole breast RT post breast-conserving surgery (BCS) reduces invasive breast cancer recurrence-free interval (IBCR-FI) in patients (pts) with pathologically positive axillary (PPAx) nodes who are ypN0 after neoadjuvant chemotherapy (NC): NRG Oncology/NSABP B-51/RTOG 1304 [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 OT2-04-01.

NRG Oncology/NSABP B-51/RTOG 1304: Phase III trial to determine if chest wall and regional nodal radiotherapy (CWRNRT) post mastectomy (Mx) or the addition of RNRT to breast RT post breast-conserving surgery (BCS) reduces invasive breast cancer recurrence-free interval (IBCR-FI) in patients (pts) with positive axillary (PAx) nodes who are ypN0 after neoadjuvant chemotherapy (NC).

NRG Oncology/NSABP B-51/RTOG 1304: Phase III trial to determine if chest wall and regional nodal radiotherapy (CWRNRT) post mastectomy (Mx) or the addition of RNRT to breast RT post breast-conserving surgery (BCS) reduces invasive breast cancer recurrence-free interval (IBCR-FI) in patients (pts) with positive axillary (PAx) nodes who are ypN0 after neoadjuvant chemotherapy (NC).

Abstract OT2-03-02: NRG oncology/NSABP B-51/RTOG 1304: Phase III trial to determine if chest wall and regional nodal radiotherapy (CWRNRT) post mastectomy (Mx) or the addition of RNRT to breast RT post breast-conserving surgery (BCS) reduces invasive breast cancer recurrence-free interval (IBCR-FI) in patients (pts) with positive axillary (PAx) nodes who are ypN0 after neoadjuvant chemotherapy (NC)

Abstract Background: This phase III post-NC trial evaluates if CWRNRT post-Mx or whole breast irradiation (WBI) with RNRT after BCS significantly reduces the IBCR-FI rate in pts with PAx nodes that are negative after NC. Secondary aims are OS, LRR-FI, DR-FI, DFS-DCIS, second primary cancer, and comparison of RT effect on cosmesis in reconstructed Mx pts. Correlative science examines RT effect by tumor subtype, molecular outcome predictors for residual disease pts, and predictors for the degree of reduction in locoregional recurrence. Methods: Clinical T1-3, N1 IBC PAx nodes (FNA or core needle biopsy) pts complete ≥8 weeks of NC (anthracycline and/or taxane). HER2+ pts receive anti-HER2 therapy. Following NC, BCS or Mx, sentinel node biopsy (≥2 nodes) and/or Ax dissection with histologically negative nodes is performed. ER/PR and HER-2neu status before NC is required. Pts receive required systemic therapy. Radiation credentialing with a facility questionnaire/case benchmark is required. Random assignment for Mx pts is to no CWRNRT or CWRNRT and for BCS pts to WBI or WBI+RNRT. Statistics: 1636 pts to be enrolled over 5 yrs (definitive analysis at 7.5 yrs). Study is powered at 80% to test that RT reduces the annual hazard rate of events for IBCR-FI by 35% for an absolute risk reduction of 4.6% (5-yr cumulative rate). Intent-to-treat analysis with 3 interim analyses (43, 86, and 129 events) and a 4th/final analysis at 172 events. Pt-reported outcomes focusing on RT effect will be provided by 736 pts before random assignment and at 3, 6, 12, and 24 mos. Accrual as of 6-12-17 is 645 (39.43%). Contacts: Protocol: CTSU member website https://www.ctsu.org. Questions: NRG Oncology Pgh Clin Coord Dpt: 1-800-477-7227 or ccd@nsabp.org. Pt entry: OPEN at https://open.ctsu.org or the OPEN tab on CTSU member website. Support: U10 CA-2166; -180868, -180822; 189867; Elekta. Citation Format: Mamounas EP, Bandos H, White JR, Julian TB, Khan AJ, Shaitelman SF, Torres MA, Vicini FA, Ganz PA, McCloskey SA, Paik S, Gupta N, Li XA, DiCostanzo DJ, Curran Jr WJ, Wolmark N. NRG oncology/NSABP B-51/RTOG 1304: Phase III trial to determine if chest wall and regional nodal radiotherapy (CWRNRT) post mastectomy (Mx) or the addition of RNRT to breast RT post breast-conserving surgery (BCS) reduces invasive breast cancer recurrence-free interval (IBCR-FI) in patients (pts) with positive axillary (PAx) nodes who are ypN0 after neoadjuvant chemotherapy (NC) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT2-03-02.

Cytoplasmic Cyclin E Mediates Resistance to Aromatase Inhibitors in Breast Cancer.

Purpose: Preoperative aromatase inhibitor (AI) therapy has demonstrated efficacy in hormone receptor (HR)-positive postmenopausal breast cancer. However, many patients have disease that is either intrinsically resistant to AIs or that responds initially but develops resistance after prolonged exposure. We have shown that patients with breast tumors expressing the deregulated forms of cyclin E [low molecular weight forms (LMW-E)] have poor overall survival. Herein, we hypothesize that LMW-E expression can identify HR-positive tumors that are unresponsive to neoadjuvant AI therapy due to the inability of AIs to induce a cytostatic effect.Experimental Design: LMW-E was examined in breast cancer specimens from 58 patients enrolled in the American College of Surgeons Oncology Group Z1031, a neoadjuvant AI clinical trial. The mechanisms of LMW-E-mediated resistance to AI were evaluated in vitro and in vivo using an inducible model system of cyclin E (full-length and LMW-E) in aromatase-overexpressing MCF7 cells.Results: Breast cancer recurrence-free interval was significantly worse in patients with LMW-E-positive tumors who received AI neoadjuvant therapy, compared with those with LMW-E negative tumors. Upon LMW-E induction, MCF7 xenografts were unresponsive to letrozole in vivo, resulting in increased tumor volume after treatment with AIs. LMW-E expression overcame cell-cycle inhibition by AIs in a CDK2/Rb-dependent manner, and inhibition of CDK2 by dinaciclib reversed LMW-E-mediated resistance, whereas treatment with palbociclib, a CDK4/6 inhibitor, did not.Conclusions: Collectively, these findings suggest that cell-cycle deregulation by LMW-E mediates resistance to AIs and a combination of CDK2 inhibitors and AIs may be an effective treatment in patients with HR-positive tumors that express LMW-E. Clin Cancer Res; 23(23); 7288-300. ©2017 AACR.

NRG Oncology/NSABP B-51/RTOG 1304: Phase III trial to determine if chest wall and regional nodal radiotherapy (CWRNRT) post mastectomy (Mx) or the addition of RNRT to breast RT post breast-conserving surgery (BCS) reduces invasive breast cancer recurrence free interval (IBCRFI) in patients (pts) with positive axillary (PAx) nodes who are ypN0 after neoadjuvant chemotherapy (NC).

TPS589 Background: This phase III post-NC trial evaluates if CWRNRT post-Mx or whole breast irradiation (WBI) with RNRT after BCS significantly reduces the IBCR-FI rate in pts with PAx nodes that are negative after NC. Secondary aims are OS, LRR-FI, DR-FI, DFS-DCIS, second primary cancer, and comparison of RT effect on cosmesis in reconstructed Mx pts. Correlative science examines RT effect by tumor subtype, molecular outcome predictors for residual disease pts, and predictors for the degree of reduction in locoregional recurrence. Methods: Clinical T1-3, N1 IBC PAx nodes (FNA or core needle biopsy) pts complete ≥12 weeks of NC (anthracycline and/or taxane). HER2+ pts receive anti-HER2 therapy. Following NC BCS or Mx, sentinel node biopsy (≥3 nodes) and/or Ax dissection with histologically negative nodes is performed. ER/PR and HER-2neu status before NC is required. Pts receive required systemic therapy. Radiation credentialing with a facility questionnaire/case benchmark is required. Random assignment for Mx pts is to no CWRNRT or CWRNRT and for BCS pts to WBI or WBI RNRT. Statistics: 1636 pts to be enrolled over 5 yrs (definitive analysis at 7.5 yrs). Study is powered at 80% to test that RT reduces the annual hazard rate of events for IBCR-FI by 35% for an absolute risk reduction of 4.6% (5-yr cumulative rate). Intent-to-treat analysis with 3 interim analyses (43, 86, and 129 events) and a 4th/final analysis at 172 events. Pt-reported outcomes focusing on RT effect will be provided by 736 pts before random assignment and at 3, 6, 12, and 24 mos. Accrual as of 2-2-17 is 534 (32.64%). Contacts: Questions: NRG Oncology Pgh Clin Coord Dpt: 1-800-477-7227 or ccd@nsabp.org . Support: U10 CA-2166; -180868, -180822; 189867; Elekta Clinical trial information: NCT01872975.

Abstract OT2-03-01: NRG oncology/NSABP B-51/RTOG 1304: A phase III superiority clinical trial designed to determine if chest wall and regional nodal radiotherapy (CWRNRT) post mastectomy (Mx) or the addition of RNRT to breast RT post breast-conserving surgery (BCS) will reduce invasive cancer events in patients (pts) with positive axillary (Ax) nodes and convert to ypN0 after neoadjuvant chemotherapy (NC)

Abstract Background: This phase III post-NC trial evaluates if CWRNRT post Mx or whole breast irradiation (WBI) with RNRT after BCS significantly reduces the invasive breast cancer recurrence-free interval (IBC-RFI) rate in pts presenting with positive Ax nodes that are pathologically negative after NC. Secondary aims are OS, LRRFI, DRFI, DFS-DCIS, and second primary cancer, as well as comparing RT effect on cosmesis in reconstructed Mx pts. Correlative science studies examine RT effect by tumor subtype, molecular outcome predictors for residual disease pts, and predictors for the degree of reduction in loco-regional recurrence. Methods: Clinical T1-3, N1 IBC pts with positive Ax nodes (FNA or core needle biopsy) complete ≥8 wks of NC (anthracycline and/or taxane). HER2-positive pts receive anti-HER2 therapy (tx). After NC, BCS or Mx is performed with a sentinel node biopsy (≥2 nodes) and/or Ax dissection with histologically negative nodes. ER/PR and HER2 neu status before NC is required. Pts receive required systemic tx. Radiation credentialing with a facility questionnaire and a case benchmark is required. Randomization for Mx pts is to no CWRNRT or CWRNRT and for BCS pts to WBI or WBI+RNRT. Statistics: 1636 pts to be enrolled over 5 yrs with definitive analysis at 7.5 yrs. Study is powered at 80% to test that RT reduces the annual hazard rate of events for IBCR-FI by 35% for an absolute risk reduction in the 5-yr cumulative rate of 4.6%. Intent-to-treat analysis with 3 interim analyses at 43, 86, and 129 events, with a 4th/final analysis at 172 events will occur. Accrual as of 6/13/16 is 356. Pt-reported outcomes focusing on RT effect will be obtained from 736 pts before randomization and at 3, 6, 12, and 24 months. Contacts: Protocol: CTSU member website https://www.ctsu.org. Questions: NRG Oncology Pgh Clin Coord Dpt: 1-800-477-7227 or ccd@nsabp.org. Pt entry: OPEN at https://open.ctsu.org or the OPEN tab on CTSU member website. Support: U10 CA-2166; -180868, -180822; -189867; Elekta. Citation Format: Mamounas EP, Bandos H, White JR, Julian TB, Khan AJ, Shaitelman SF, Torres MA, Vicini FA, Ganz PA, McCloskey SA, Paik S, Gupta N, Li XA, DiCostanzo DJ, Curran, Jr WJ, Wolmark N. NRG oncology/NSABP B-51/RTOG 1304: A phase III superiority clinical trial designed to determine if chest wall and regional nodal radiotherapy (CWRNRT) post mastectomy (Mx) or the addition of RNRT to breast RT post breast-conserving surgery (BCS) will reduce invasive cancer events in patients (pts) with positive axillary (Ax) nodes and convert to ypN0 after neoadjuvant chemotherapy (NC) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT2-03-01.

NRG Oncology/NSABP B-51/RTOG 1304: Phase III trial to determine if chest wall and regional nodal radiotherapy (CWRNRT) post mastectomy (Mx) or the addition of RNRT to breast RT post breast-conserving surgery (BCS) reduces invasive breast cancer recurrence free interval (IBCRFI) in patients (pts) with positive axillary (PAx) nodes who are ypN0 after neoadjuvant chemotherapy (NC).

NRG Oncology/NSABP B-51/RTOG 1304: Phase III trial to determine if chest wall and regional nodal radiotherapy (CWRNRT) post mastectomy (Mx) or the addition of RNRT to breast RT post breast-conserving surgery (BCS) reduces invasive breast cancer recurrence free interval (IBCRFI) in patients (pts) with positive axillary (PAx) nodes who are ypN0 after neoadjuvant chemotherapy (NC).

Abstract OT2-02-02: NRG Oncology/NSABP B-51/RTOG 1304: A phase III clinical trial to determine if chest wall and regional nodal radiotherapy (CWRNRT) post mastectomy (Mx) or the addition of RNRT to breast RT post breast-conserving surgery (BCS) will reduce invasive cancer events in patients (pts) with positive axillary (Ax) nodes who are ypN0 after neoadjuvant chemotherapy (NC)

Abstract Background: This phase III post-NC trial will evaluate if CWRNRT post Mx or whole breast irradiation (WBI) with RNRT after BCS significantly reduces the invasive breast cancer recurrence-free interval (IBC-RFI) rate in pts presenting with positive Ax nodes that are negative after NC. Secondary aims are OS, LRRFI, DRFI, DFS-DCIS, and second primary cancer as well as comparing RT effect on cosmesis in reconstructed Mx pts. Correlative science examines RT effect by tumor subtype, molecular outcome predictors for residual disease pts, and predictors for the degree of reduction in loco-regional recurrence. Methods: Clinical T1-3, N1 IBC pts with positive Ax nodes (FNA or core needle biopsy) complete ≥12 wks of NC (anthracycline and/or taxane). HER2-positive pts receive anti-HER2 therapy (tx). After NC BCS or Mx is performed with a sentinel node biopsy (≥3 nodes) and/or Ax dissection with histologically negative nodes. ER/PR and HER-2 neu status before NC is required. Pts receive required systemic tx. Radiation credentialing with a facility questionnaire and a case benchmark is required. Randomization for Mx pts is to no CWRNRT or CWRNRT and for BCS pts to WBI or WBI RNRT. Statistics: 1,636 pts to be enrolled over 5 yrs with definitive analysis at 7.5 yrs. Study is powered at 80% to test that RT reduces the annual hazard rate of events for IBCR-FI by 35% for an absolute risk reduction in the 5-yr cumulative rate of 4.6%. Intent-to-treat analysis with 3 interim analyses at 43, 86, and 129 events, with a 4th/final analysis at 172 events will occur. Accrual as of 6/4/15 is 143. Pt-reported outcomes focusing on RT effect will be provided by 736 pts before randomization and at 3, 6, 12, and 24 months. Contacts: Protocol: CTSU member website https://www.ctsu.org. Questions: NRG Oncology Pgh Clin Coord Dpt: 1-800-477-7227 or ccd@nsabp.org. Pt entry: OPEN at https://open.ctsu.org or the OPEN tab on CTSU member website. Support: U10 CA-2166; -180868, -180822; -189867; Elekta. Citation Format: Mamounas EP, Bandos H, White JR, Julian TB, Khan AJ, Shaitelman SF, Torres MA, Vicini FA, Ganz PA, McCloskey SA, Paik S, Gupta N, Li XA, DiCostanzo DJ, Costantino JP, Curran Jr WJ, Wolmark N. NRG Oncology/NSABP B-51/RTOG 1304: A phase III clinical trial to determine if chest wall and regional nodal radiotherapy (CWRNRT) post mastectomy (Mx) or the addition of RNRT to breast RT post breast-conserving surgery (BCS) will reduce invasive cancer events in patients (pts) with positive axillary (Ax) nodes who are ypN0 after neoadjuvant chemotherapy (NC). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT2-02-02.

Abstract OT1-3-02: Will chest wall and regional nodal radiotherapy post mastectomy or the addition of regional nodal radiotherapy to breast radiotherapy post lumpectomy reduce the rate of invasive cancer events in patients with positive axillary nodes who convert to ypN0 af

Abstract Background This phase III randomized post-neoadjuvant chemotherapy trial will evaluate if chest wall and regional nodal XRT (CWRNRT) after mastectomy or whole breast irradiation (WBI) with RNRT after breast-conserving surgery significantly reduces the rate of events for invasive breast cancer recurrence-free interval (IBCR-FI) in patients who present with histologically positive axillary nodes but become histologically negative axillary nodes after neoadjuvant chemotherapy. Secondary aims are OS, LRR-FI, DRFI, DFS-DCIS, and second primary cancer. HYPOTHESIS: Can We Use Tumor and Nodal Response to Neoadjuvant Chemotherapy in Order to Individualize the Use of L-R XRT? Correlative science will examine the effect of RT by tumor subtype, molecular predictors of outcome for patients with residual disease, and the development of predictors of degree of reduction in loco-regional recurrence. Methods Eligible patients with clinical T1-3, N1 breast cancer with pathologic axillary nodal involvement (positive FNA or core needle biopsy) must complete ≥12 weeks of neoadjuvant chemotherapy (anthracycline and/or taxane-based regimen). HER2-positive patients must receive neoadjuvant trastuzumab or other anti-HER2 therapy. After neoadjuvant chemotherapy either breast-conserving surgery or mastectomy will be performed. At the time of surgery, all removed axillary nodes must be histologically free from cancer. 3 or more histologically negative sentinel nodes are acceptable to determine axillary nodal involvement. ER/PR and HER-2 neu status before neoadjuvant chemotherapy is required. All patients will receive additional required systemic therapy. Site radiation credentialing with a facility questionnaire and case benchmarking is required. Randomization for mastectomy patients will be to no CWRNRT or CWRNRT and for breast-conserving surgery patients to WBI or WBI RNRT. Statistical Considerations 1636 patients will be enrolled over 5 years with definitive analysis at 7.5 years. The study is powered at 80% to test the main hypothesis that RT reduces the annual hazard rate of events for IBCR-FI by 35% for an absolute risk reduction in the 5-year cumulative rate of 4.6%. Analysis will be on intent-to-treat with 3 formal interim analyses at 43, 86, and 129 events, with a 4th/final analysis at 172 events. Current accrual is 37. (as of 6-10-14) 736 enrolled patients will be evaluated with targeted patient-reported outcome instruments focusing on the effect of RT. Patient assessments will be prior to randomization and then at 3, 6, 12, and 24 months. Contact Information Study protocol information can be found under the protocol-specific web page on the CTSU member web site https://www.ctsu.org. For protocol-specific questions contact – NRG Oncology Pittsburgh Clinical Coordinating Department. Phone: 1-800-477-7227. Email: ccd@nsabp.org. All investigators will enroll patients by accessing OPEN at https://open.ctsu.org or from the OPEN tab on the CTSU members’ side of the web site. Support: NCI PHS U10-CA-12027, -69651, -37377, -69974, and -2166. Citation Format: Eleftherios P Mamounas, Hanna Bandos, Julia R White, Thomas B Julian, Atif J Khan, Simona F Shaitelman, Mylin A Torres, Susan A McCloskey, Frank A Vicini, Patricia A Ganz, Soonmyung Paik, Nilendu Gupta, Joseph P Costantino, Walter J Curran Jr, Norman Wolmark. Will chest wall and regional nodal radiotherapy post mastectomy or the addition of regional nodal radiotherapy to breast radiotherapy post lumpectomy reduce the rate of invasive cancer events in patients with positive axillary nodes who convert to ypN0 af [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT1-3-02.

Physical Activity, Weight Control, and Breast Cancer Risk and Survival: Clinical Trial Rationale and Design Considerations

Substantial observational epidemiological evidence exists that physical activity and weight control are associated with decreased risk of postmenopausal breast cancer. Uncertainty remains regarding several aspects of these associations, including the effect of possible confounding factors on these associations. We present the rationale and design for two randomized controlled trials that can help resolve this uncertainty. In a 5-year prevention trial conducted among women at high risk of breast cancer, the primary endpoint would be breast cancer incidence. For a comparable survivorship trial, the primary endpoint would be the disease-free interval and secondary endpoints would be breast cancer recurrence-free interval, second primary breast cancer, and total invasive plus in situ breast cancer. A set of inclusion and exclusion criteria is proposed for both trials. Intervention goals are the same for both trials. Goals for the weight control intervention would be, for women whose body mass index (BMI) is greater than 25 kg/m(2), to lose 10% of body weight and, for women whose BMI is less than or equal to 25 kg/m(2), to avoid weight gain. The goal for the physical activity intervention would be to achieve and maintain regular participation in a moderate-intensity physical activity program for a total of 150-225 minutes over at least 5 days per week. Sample size calculations are based on alternative assumptions about hazard ratio, adherence, follow-up duration, and power and are presented for the primary prevention and survivorship trials. Although both studies could enhance our understanding of breast cancer etiology and benefit public health, practical considerations, including smaller sample size, ease of recruitment, and reduced likelihood of early termination, favor the survivorship trial at this time.