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Background: Breast conserving surgery (BCS) is typically followed by adjuvant radiotherapy (RT) based on several landmark trials demonstrating improvements in disease control and survival. Since completion of these historical trials, the advent of molecular subtyping has revealed that breast cancer is not a single disease entity, but rather a class of cancers with differential risk profiles. We evaluated whether RT could be safely omitted following BCS for patients with the most favorable subtype as defined by the Prosigna PAM50 assay. Methods: We conducted a multicenter prospective single-arm cohort study with IRB approval and an FDA investigational device exemption (IDE). Eligible patients were women 50 to 75 years of age (inclusive) who had undergone BCS revealing tumors ≤2cm in size, that were estrogen or progesterone receptor positive (HR+), HER2 negative, grade 1-2, node negative (N0), with negative excision margins (no ink on tumor). Intent to take endocrine therapy was required. Upon registration, tumors were submitted for central Prosigna testing and those with Risk of Recurrence (ROR) score ≤40 were deemed eligible for the investigational omission of RT. The primary endpoint was the 5-year locoregional recurrence rate (LRR). Anticipating a total of 345 RT-omitting patients to enroll over 3.5 years, the study was designed with 90% power to exclude a 5-year LRR of 5% using a one-sample exponential test with one-sided type I error of 0.025. Results: From 2016 to 2020, 671 patients were registered from 13 centers, inclusive of affiliated regional network sites. Of these, 382 patients had a ROR Score ≤40 and opted to forego RT, comprising the main intention-to-treat (ITT) study population. Median age was 65 years (range 50 to 75), and median tumor size was 0.9 cm (range 0.1 to 2.0 cm). At a median follow-up of 26.9 months, 12 events were observed: 4 patients had ipsilateral in-breast recurrences, 7 had contralateral breast cancers, and 1 developed an unrelated melanoma. There were no regional-nodal or distant recurrences. The 2-year cumulative rate of LRR was 0.3% (95% CI: 0 – 1.0%). Of the 4 ipsilateral breast recurrences, 2 were in the same quadrant as the original primary tumor. Conclusion: In this preliminary report of the PRECISION trial, patients 50-75 years of age undergoing BCS and endocrine therapy for pT1N0 HR+ HER2-negative breast cancer with ROR score ≤40 had exceedingly low rates of LRR in the absence of adjuvant RT at a median follow-up of 26.9 months. Additional follow-up is required to determine whether these favorable results are durable. Citation Format: Lior Z. Braunstein, Julia Wong, Deborah A. Dillon, Yu-Hui Chen, Paul Catalano, Oren Cahlon, Mahmoud B. El-Tamer, Rachel Jimenez, Atif Khan, Carmen Perez, Rinaa Punglia, Ron Shiloh, Laura Warren, David Wazer, Jean Wright, Elizabeth Buckley, Tari King, Simon Powell, Eric Winer, Jennifer Bellon. Preliminary report of the PRECISION Trial (Profiling Early Breast Cancer for Radiotherapy Omission): A Phase II Study of Breast-Conserving Surgery Without Adjuvant Radiotherapy for Favorable-Risk Breast Cancer [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 OT1-12-02.

Postmastectomy radiation therapy (PMRT) is a mainstay of local therapy for many breast cancer patients. Patients undergoing mastectomy typically are offered options for breast reconstruction. For patients who are candidates for PMRT, there are ongoing challenges with combining optimal radiation technique to prioritize oncologic outcomes, against the goals of minimizing toxicity and achieving the best reconstruction outcomes. The process by which these decisions are made continues to evolve as surgical and radiation techniques have improved and expanded, and as more patients with different risk profiles for local recurrence are receiving PMRT. We review the considerations regarding the different types of reconstruction and timing with radiation treatment. We also review the technical radiation consideration such as dose-fractionation, use of bolus and scar boost, exploring the controversies associated with the nuanced decisions regarding radiation and reconstructive surgery which are influenced by variables that are under continued investigation.

The after mapping of the axilla: radiotherapy or surgery (AMAROS) trial concluded that for patients with cT1-2 N0 breast cancer and one or two positive sentinel lymph nodes (SLNs), axillary radiotherapy (AxRT) provides equivalent locoregional control and a lower incidence of lymphedema compared with axillary lymph node dissection (ALND). The study prospectively assessed how often ALND could be replaced by AxRT in a consecutive cohort of patients undergoing mastectomy for cT1-2 N0 breast cancer. In November 2015, our multidisciplinary group agreed to omit routine intraoperative SLN evaluation for cT1-2 N0 patients undergoing upfront mastectomy and potentially eligible for postmastectomy radiation therapy (PMRT), including those 60 years of age or younger and those older than 60 years with high-risk features. Patients with one or two positive SLNs on final pathology were reviewed to determine whether PMRT including the full axilla was an appropriate alternative to ALND. From November 2015 to December 2016, 154 patients met the study criteria, and 114 (74%) formed the final study cohort. Intraoperative SLN evaluation was omitted for 76 patients (67%). Of these patients, 20 (26%) had one or two positive SLNs, and 14 of these patients received PMRT + AxRT as an alternative to ALND. Three patients returned for ALND, and three patients were observed. On univariate analysis, tumor size, LVI, number of positive lymph nodes, and receipt of chemotherapy were associated with receipt of PMRT. For the majority of patients with one or two positive SLNs, ALND was avoided in favor of PMRT + AxRT. With appropriate multidisciplinary strategies, intraoperative evaluation of the SLN and immediate ALND can be avoided for patients meeting the AMAROS criteria and eligible for PMRT.

Background: Radiation therapy (RT) following breast conserving surgery (BCS) is known to improve locoregional and distant control in women with invasive breast cancer; however, RT does pose significant cost and potential risk, including concern for cardiopulmonary toxicity and secondary malignancy. Randomized trials show that the omission of RT among older women with otherwise favorable-risk breast cancer does not affect overall survival (OS) at 10 years, and modestly increases the risk of local recurrence (LR). Nevertheless, there is little prospective support for RT omission in younger women. Moreover, risk stratification in the randomized prospective studies to date relies on limited methods with potentially low fidelity at distinguishing luminal subtypes. Enhanced molecular profiling techniques could better discern tumor biology and, in turn, more precisely assess risk. PAM-50 is an expression profile of 50 genes used to classify breast cancer intrinsic subtype with consequent prognostic implications. The goal of this study is to identify low-risk breast cancer patients with luminal A subtype who may feasibly omit RT from their therapeutic regimen. Methods: This is a phase II prospective cohort study (NCT02653755) designed to assess the safety of treatment de-escalation (omission of RT) in women with favorable-risk invasive breast cancer following BCS. Eligibility criteria include female patients with invasive breast cancer, age 50-75, with tumors less than or equal to 2cm, negative surgical margins, ER+ or PR+ and HER2- disease, grade 1 or 2, no lymph node involvement, and no plans for chemotherapy or biologic therapy, who are eligible for and willing to receive endocrine therapy. Tumor samples from eligible patients will undergo PAM-50 transcriptional profiling using the Nanostring Prosigna assay. A low Risk of Recurrence (ROR) score, corresponding to the luminal A subtype, will permit patients to forego radiotherapy should they so choose. The primary endpoint is 5-year risk of local or regional recurrence of invasive or in situ breast carcinoma within the ipsilateral breast or regional lymph nodes. Study enrollment began in May 2016. Citation Format: Mira A. Patel, Deborah A. Dillon, Giulia Digiovanni, Yu-Hui Chen, Paul Catalano, Carmen Perez, David Wazer, Jean Wright, Rachel Jimenez, Eric Winer, Julia Wong, Jennifer Bellon, Lior Z. Braunstein. PRECISION (Profiling early breast cancer for radiotherapy omission): A phase II study of breast-conserving surgery without adjuvant radiotherapy for favorable-risk breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT271.

Background: Young women with breast cancer (BC) often receive aggressive local therapy and are more likely to undergo (bilateral) mastectomy and receive postmastectomy radiation (RT) than older women. Our previous work suggested better quality of life (QOL) outcomes among women undergoing breast conserving therapy (BCT) vs. mastectomy, even with reconstruction (recon), although limited data was available regarding recon. In the current analysis, we sought to understand the impact of recon, accounting for RT, on long-term satisfaction and QOL. Methods: Between 10/2016-11/2017, we administered the BREAST-Q, a validated patient-reported outcomes measure designed to evaluate satisfaction and QOL after breast cancer surgery and recon, to 743 women in the Young Women’s Breast Cancer Study, a multi-site prospective cohort that enrolled women diagnosed (dx’d) at age < 40 from 2006-2016. Demographic and treatment information was obtained by surveys and chart review. Recon was defined as autologous, implant or complex (combination of autologous and implant). Mean BREAST-Q scores for each domain (breast satisfaction, physical, psychosocial, and sexual) were compared by recon types and stratified by receipt of RT; higher BREAST-Q scores (range: 0-100) indicate better QOL. Linear regression was used to identify predictors of BREAST-Q scores. Results: 584 women with Stage 0-3 BC completed the Breast-Q at a median of 5.7 [range 2-10] years from dx), 357 (61%) had mastectomy and recon and were included in the analytic sample. Median age at dx was 36 years; 85% had stage 0, 1 or 2 disease; 41% received RT and 76% underwent bilateral mastectomy. 90.5% underwent immediate recon; of which 65.5% were tissue expander placement. Definitive recon included autologous tissue in 16%; implants in 81% and complex recon in 3%. Mean BREAST-Q breast satisfaction, psychosocial, and physical well-being scores differed based on recon type accounting for RT (Table 1). Significantly lower scores for breast satisfaction were seen in women having implant +RT. Scores were not impacted by bilateral procedure, timing of recon, use of tissue expander, extent of axillary surgery, cancer stage or other treatment factors. In multivariate analyses, receipt of RT, lymphedema and implant-based recon were associated with lower breast satisfaction scores. Physical well-being scores were lower for those with complex recon, for non-White women, for women who reported being financially uncomfortable, for those with lymphedema, and for those 25, and for those who reported being financially uncomfortable. Sexual well-being scores were lower for women with a BMI >25 and for those who reported being financially uncomfortable. Conclusion Type of recon and receipt of radiation among young survivors who undergo mastectomy and recon for early breast cancer appears to have a differential impact on satisfaction and QOL. Our finding of lower breast satisfaction among young women who received RT, particularly after implant recon, underscores the importance of counseling regarding surgical options, especially for women who may receive RT after mastectomy and who are candidates for BCT. Table 1. Unadjusted BREAST-Q scores stratified by RTBREAST-Q DomainAutologous -RT N=29Autologous +RT N=27Implant -RT N=174Implant +RT N=113Complex N=13Global p-valueSatisfaction with Breasts, mean (sd)67 (19)63 (18)64 (18)53 (18)58 (22) Citation Format: Laura Dominici, Jiani Hu, Hee Jeong Kim, Tari King, Kathryn Ruddy, Rulla Tamimi, Jeffrey Peppercorn, Lidia Schapira, Virginia Borges, Stephen Come, Ellen Warner, Julia Wong, Ann Partridge, Shoshana Rosenberg. BREAST-Q satisfaction and quality of life outcomes in young women undergoing mastectomy and reconstruction for breast cancer [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 PD6-1.

Importance The use of a radiotherapy (RT) boost to the tumor bed after whole-breast RT (WBRT) for ductal carcinoma in situ (DCIS) is largely extrapolated from invasive cancer data, but robust evidence specific to DCIS is lacking. Objective To compare ipsilateral breast tumor recurrence (IBTR) in women with DCIS treated with vs without the RT boost after breast-conserving surgery and WBRT. Design, Setting, and Participants This retrospective analysis pooled deidentified patient-level data from 10 academic institutions in the United States, Canada, and France from January 1, 1980, through December 31, 2010. All patients had newly diagnosed pure DCIS (no microinvasion), underwent breast-conserving surgery, and received WBRT with or without the boost with a minimum of 5 years of follow-up required for inclusion in the analysis. Given the limited events after WBRT, an a priori power analysis was conducted to estimate the DCIS sample size needed to detect the anticipated benefit of the boost. Data were uniformly recoded at the host institution and underwent primary and secondary reviews before analysis. Sample size calculations (ratio of patients who received the boost dose to those who did not, 2:1; α = .05; power = 80%) estimated that 2982 cases were needed to detect a difference of at least 3%. The final analysis included 4131 patients (2661 in the boost group and 1470 in the no-boost group) with a median follow-up of 9 years and media boost dose of 14 Gy. Data were collected from July 2011 through February 2014 and analyzed from March 2014 through August 2015. Interventions Radiotherapy boost vs no boost. Main Outcomes and Measures Ipsilateral breast tumor recurrence. Results The analysis included 4131 patients (median [SD] age, 56.1 [10.9] years; range, 24-88 years). Patients with positive margins, unknown estrogen receptor status, and comedo necrosis were more likely to have received an RT boost. For the entire cohort, the boost was significantly associated with lower IBTR (hazard ratio [HR], 0.73; 95% CI, 0.57-0.94; P = .01) and with IBTR-free survival (boost vs no-boost groups) of 97.1% (95% CI, 0.96-0.98) vs 96.3% (95% CI, 0.95-0.97) at 5 years, 94.1% (95% CI, 0.93-0.95) vs 92.5% (95% CI, 0.91-0.94) at 10 years, and 91.6% (95% CI, 0.90-0.93) vs 88.0% (95% CI, 0.85-0.91) at 15 years. On multivariable analysis accounting for confounding factors, the boost remained significantly associated with reduced IBTR (HR compared with no boost, 0.68; 95% CI, 0.50-0.91; P = .01) independent of age and tamoxifen citrate use. Conclusions and Relevance This patient-level analysis suggests that the RT boost confers a statistically significant benefit in decreasing IBTR across all DCIS age groups, similar to that seen in patients with invasive breast cancer. These findings suggest that a DCIS RT boost to the tumor bed could be considered to provide an added incremental benefit in decreasing IBTR after a shared discussion between the patient and her radiation oncologist.

Axillary node dissection (ALND) is the standard of care for patients who have a positive sentinel lymph node (SLN) on sentinel lymph node biopsy (SLNB). We sought to identify a low-risk patient population with positive SLN that may not need cALND. We analyzed SLNB for breast cancer at our institutions between 1999 and 2007. We identified 130 patients who had a positive SLN but did not undergo completion ALND. We evaluated clinical data, adjuvant treatment patterns and intermediate locoregional and distant events. The median patient age was 50; 19% had N0(i+) disease, 53% had micrometastatic (N1mi) disease, and 28% had macrometastasis. Eighty-eight percent of patients underwent radiation therapy; 66 patients (51%) had documented nodal radiation (of these 50 were treated with three fields and 14 with high tangents. Local recurrence in the breast occurred in two patients (2%) and nine patients (7%) developed distant metastases; there were no axillary/nodal recurrences. In this highly selected group of patients who had a positive SLNB but did not undergo cALND, we observed no axillary recurrences.

Background: Radiation therapy (RT) following breast conserving surgery (BCS) is well-known to improve outcomes for invasive breast cancer. However, RT can be resource-intensive, disruptive, and confers a small risk of long-term adverse effects. In addition, reports have suggested that not all patients stand to benefit equally from RT, with certain features portending an excellent prognosis regardless of the adjuvant treatment approach. Specifically, favorable luminal A cancers exhibit a 10-year locoregional recurrence (LRR) rate of 2% following BCS and RT. However, distinguishing luminal A cancers from their less-favorable luminal B counterparts remains a challenge. This trial employs molecular profiling to identify favorable-risk, early-stage breast cancer patients who may safely omit RT following BCS. Methods: To identify a low-risk, luminal A cohort, we are employing well-characterized clinicopathologic parameters in addition to molecular profiling. Eligible patients are 50-75 years of age and must have invasive breast cancer ≤2 cm (T1), that is estrogen or progesterone receptor positive, low- or intermediate-grade, without HER2 amplification, and with negative margins (no ink on tumor) following BCS. Following resection, tumor samples undergo prediction analysis of microarray 50 (PAM50) profiling via the NanoString Prosigna assay to characterize intrinsic biologic subtype. Patients with tumors classified as luminal A (low risk of recurrence score) are eligible for the omission of RT. The trial is a single-arm prospective cohort study designed to assess the viability of RT omission in this favorable population. The primary endpoint is LRR at 5 years; a rate of Results: PRECISION opened to accrual in April 2016 and, as of October 2017 has registered 57 patients to undergo molecular risk profiling. Of these, 2 (3.5%) withdrew consent prior to receiving their PAM50 results and 11 (19.3%) were ineligible based on their risk-of-recurrence score, leaving 43 patients eligible for the omission of RT. Of these, 4 (7.0%) ultimately chose to undergo RT, while 39 (68.4%) opted to omit RT on the investigational arm of the study. Conclusions: The omission of RT is of interest to low-risk breast cancer patients. The safety and feasibility of this approach is currently being studied. Citation Format: Lior Zvi Braunstein, Ashley Iannone, Alphonse G. Taghian, Julia Wong, Jennifer Bellon, Jay R. Harris. PRECISION (Profiling Early Breast Cancer for radiotherapy Omission): An ongoing phase II study of breast-conserving surgery without adjuvant radiotherapy for favorable-risk breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3692.

Optimal beam geometry for kilovoltage cone-beam tomosynthesis (CB-TS) imaging for the set-up of 20 patients with breast cancer was analyzed and presented for prone and supine scenarios. Gantry angles and field sizes that allow maximum clearance and minimum dose to normal organs from kilovoltage imaging were determined for medial and lateral arcs. Optimal CB-TS arc span may vary depending on patient geometry, particularly on the separation between the cavity and the chest wall. CB-TS arc angles 40 degrees were found to be optimal for the cavity to chest wall separation d>3 cm for supine set-up and d>7 cm for prone set-up. Maximum required jaw openings were 20 x 14 cm(2). Recommendations are provided for clinical implementation of CB-TS imaging for breast cancer patients.

Purpose: To evaluate the safety and feasibility of concurrent radiation therapy and paclitaxel-based adjuvant chemotherapy, given either weekly or every 3 weeks, after adjuvant doxorubicin and cyclophosphamide (AC). Methods and Materials: After definitive breast surgery and AC chemotherapy, 40 patients with operable Stage II or III breast cancer received protocol-based treatment with concurrent paclitaxel and radiation therapy. Paclitaxel was evaluated on 2 schedules, with treatment given either weekly × 12 weeks (60 mg/m 2 ), or every 3 weeks × 4 cycles (135–175 mg/m 2 ). Radiation fields and schedules were determined by the patient's surgery and pathology. The tolerability of concurrent therapy was evaluated in cohorts of 8 patients as a phase I study. Results: Weekly paclitaxel treatment at 60 mg/m 2 per week with concurrent radiation led to dose-limiting toxicity in 4 of 16 patients (25%), including 3 who developed pneumonitis (either Grade 2 [1 patient] or Grade 3 [2 patients]) requiring steroids. Efforts to eliminate this toxicity in combination with weekly paclitaxel through treatment scheduling and CT-based radiotherapy simulation were not successful. By contrast, dose-limiting toxicity was not encountered among patients receiving concurrent radiation with paclitaxel given every 3 weeks at 135–175 mg/m 2 . However, Grade 2 radiation pneumonitis not requiring steroid therapy was seen in 2 of 24 patients (8%) treated in such a fashion. Excessive radiation dermatitis was not observed with either paclitaxel schedule. Conclusions: Concurrent treatment with weekly paclitaxel and radiation therapy is not feasible after adjuvant AC chemotherapy for early-stage breast cancer. Concurrent treatment using a less frequent paclitaxel dosing schedule may be possible, but caution is warranted in light of the apparent possibility of pulmonary injury.

Purpose: To estimate the possible efficacy of axillary radiation therapy (AXRT) following a positive sentinel node biopsy (SNB), we evaluated the risk of regional nodal failure (RNF) for patients with clinical Stage I or II, clinically node-negative invasive breast cancer treated with either no dissection or a limited dissection (LD) defined as removal of 5 nodes or less followed by AXRT. Materials and Methods: From 1978 to 1987, 292 patients underwent AXRT in the absence of axillary dissection; 126 underwent AXRT following LD. The median dose to the axilla was 46 Gy. The median dose to the supraclavicular fossa was 45 Gy. Among patients found to have positive nodes on LD, adjuvant chemotherapy and tamoxifen were administered to 81% and 7% of subjects, respectively. All patients had potential 8-year follow-up. Results: Six of the 418 patients (1.4%) developed RNF as a first site of failure within 8 years. Among these 6 patients (1.4%) with RNF as the first site of failure, 4 had simultaneous distant and regional recurrences; and 2 had isolated axillary failures. Three of the 292 patients (1%) with no axillary dissection, none of 84 patients with pathologically negative nodes and 3 of 42 patients (7%) with pathologically involved nodes had RNF as a first site of failure. Radiation pneumonitis developed in 5 patients (1.2%), brachial plexopathy in 5 (1.2%) and arm edema in 4 (1.2%). In all cases, radiation pneumonitis and brachial plexopathy were transient. Conclusion: These results imply that AXRT may be an effective and safe alternative to completion dissection for treatment of the axilla following a positive SNB. Further studies comparing these two options in specific patient subgroups are needed.

Transforming growth factor-β (TGF-β) has been implicated in the in vivo resistance of the EMT-6/CTX and EMT-6/CDDP murine mammary tumors. Both of these tumors have a higher number of intratumoral vessels than the EMT-6/parent tumor. Animals bearing the resistant tumors have higher plasma levels of TGF-β than animals bearing the parent tumors; however, upon treatment with cytotoxic therapies there is a greater rise in plasma TGF-β levels in animals bearing the parent tumor than in animals bearing the resistant tumor. In situ hybridization for TGF-β mRNA and immunohistochemical staining for TGF-β protein showed that the resistant tumor levels of this growth factor are higher than those of the parent tumor prior to treatment; however, after cytotoxic therapy the increase in TGF-β is greater in the parent tumor than in the resistant tumors. Treatment of tumor-bearing animals with the naturally occurring TGF-β inhibitor decorin did not alter the sensitivity of the parent tumor to cyclophosphamide or to CDDP as determined by tumor cell survival assay. However, administration of decorin increased the sensitivity of the EMT-6/CTX tumor to cyclophosphamide and of the EMT-6/CDDP tumor to CDDP so that the drug resistance of these tumors was nearly ablated. A similar pattern was observed in the drug response of the bone marrow granulocyte-macrophage colony-stimulating factor of animals bearing each of the 3 tumors. Int. J. Cancer, 71:49–58, 1997. © 1997 Wiley-Liss, Inc.

The DNA topoisomerases I and II are the target of several clinically important antineoplastic agents which produce DNA cleavage by stabilization of the covalent DNA-protein bond with resultant cell death after DNA synthesis is attempted. Depletion of the target topoisomerase and reciprocal changes in the other occur with drug treatment. Purpose and methods: To develop empiric treatment regimens of combinations and sequences of agents directed against topoisomerase I (irinotecan/CPT-11) and II (etoposide and doxorubicin), in vivo studies were performed in mice bearing the EMT-6 mammary tumor to assess efficacy, host tolerance and the resultant biochemical changes in topoisomerase mRNA and protein. Results: At 24 h after therapy, depletion of the target topoisomerase mRNA and protein with reciprocal increases in the alternate topoisomerase mRNA and, to a lesser extent, protein were noted. No therapeutic antagonism was found with any combination or sequence of agents, and therapeutic antagonism was noted with concurrent irinotecan/etoposide and sequential doxorubicin/irinotecan. Depletion of target topoisomerases by combined therapy beyond a threshold necessary for therapeutic efficacy produced no additional benefit. Conclusions: Antineoplastic therapy with combinations of topoisomerase I and II agents is feasible and may produce therapeutic synergy. The appropriate sequence may depend on the particular agents used. The rationale for such therapy, that topoisomerases I and II may have reciprocal and compensatory interactions, is supported by the biochemical data.