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Purpose: Randomized trials have demonstrated similar local tumor control in patients treated with accelerated partial-breast irradiation (APBI) compared with whole-breast irradiation. However, the optimal APBI dose for maximizing tumor control and minimizing toxicity is uncertain., Methods and Materials: We enrolled patients ≥18 years of age with grade 1 or 2 ductal carcinoma in situ or stage I invasive breast cancer and resection margins ≥2 mm between 2003 and 2011 to a sequential dose-escalation trial using 3-dimensional conformal external beam APBI giving twice daily 4 Gy fractions with total doses of 32 Gy, 36 Gy, and 40 Gy. Most were irradiated using mini-tangents plus en-face electrons or 3 to 4 coplanar photon beams; 19 patients in the 32 Gy dose cohort were treated with protons., Results: The trial accrued 324 patients (99, 101, and 124 in 32 Gy, 36 Gy, and 40 Gy cohorts, respectively). The median follow-up was 15.2 years. The 15-year cumulative incidence of local failure in each dose cohort was 6.9%, 5%, and 3.9% in the 32 Gy, 36 Gy, and 40 Gy cohorts, respectively (log-rank P = .21) The 10-year cumulative incidence of local failure in each dose cohort was 5.2%, 5.2%, and 2.2%, respectively (log-rank P = .2). Ten-year rates of moderate or severe fibrosis by physician assessment in each cohort were 40%, 58%, and 67%, respectively (log-rank P < .01). The 10-year rates of fair or poor cosmesis by patient self-assessment were 25%, 30%, and 49% in each cohort, respectively (log-rank P < .01); physician assessment yielded similar 10-year rates of 21%, 39%, and 61%, respectively (log-rank P < .01)., Conclusions: There were no significant differences in local failure rates between 32 Gy, 36 Gy, or 40 Gy delivered in twice daily 4 Gy fractions, but fibrosis and cosmetic outcomes were worse for patients treated to the 2 higher doses. Hence, our study did not show the benefit of administering more than 32 Gy using this fractionation scheme., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: Several data sets have demonstrated a correlation between lymphovascular invasion (LVI) and locoregional recurrence (LRR). Whether the observation of "extensive LVI" is a further and incremental determinant of LRR risk is unknown. We describe clinical outcomes in women with invasive breast cancer stratified by (1) absence of LVI (neg), (2) LVI focal or suspicious (FS-LVI), (3) usual (nonextensive) LVI (LVI), and (4) extensive LVI (E-LVI)., Methods and Materials: Between December 2009 and August 2021, 8837 patients with early-stage breast cancer were treated with curative intent and were evaluable. Clinical-pathologic details were abstracted by retrospective review. The description of LVI was abstracted from pathology reports. Recurrence and survival outcomes were compared based on the extent of LVI. A matched propensity score analysis compared outcomes between patients with LVI versus E-LVI., Results: Of the 8837 patients studied, 5584 were negative, 461 had FS-LVI, 2315 had LVI, and 477 had E-LVI. Patients with E-LVI had an adverse risk profile compared with the other groups. The 5- and 10-year LRR cumulative incidence estimates in patients with E-LVI were 9.6% (95% CI, 7.1-13) and 13% (95% CI, 10-17), respectively, which were significantly higher than those observed in the usual LVI group (6.8% [5.7-7.9] and 10% [8.8-12], respectively). A statistically significant difference in LRR was demonstrated in univariable (HR, 1.4; 95% CI, 1.03-1.89; P = .029) and multivariable regression analysis (HR, 1.62; 95% CI, 1.15-2.27; P = .005) compared with nonextensive LVI. In an alternative approach, we performed a 2:1 propensity score matching analysis comparing patients with LVI to those with E-LVI. The hazard ratio for LRR (HR, 1.47; CI 1.02-2.14; P = .041) was suggestive of a higher risk associated with E-LVI., Conclusions: Our work suggests that patients with E-LVI are at a higher risk for LRR than those with usual LVI. For patients who are borderline candidates for regional nodal irradiation or post-mastectomy radiation therapy, the finding of E-LVI might be decisive in favor of intensified treatment., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: Invasive lobular carcinoma (ILC) represents 10% to 15% of invasive breast cancers with limited representation among trials of accelerated partial breast irradiation (APBI). Contemporary guidelines advise against treating ILC with APBI given a paucity of supportive evidence. Here, we evaluated oncologic outcomes among patients with ILC treated with APBI., Methods and Materials: Patients treated from 2010 to 2022 with APBI after breast conserving surgery for ILC (or mixed ILC with other histologies) were ascertained from a prospectively maintained institutional database. All patients received external beam APBI to 40 Gy in 10 daily fractions. Outcomes of interest included local recurrence (LR) and overall survival (OS)., Results: Of 1248 patients who underwent APBI at our center, the study cohort comprised 132 (11%) who had ILC, either exclusively or mixed with another histology (median age 63). Median tumor size was 1.1 cm (interquartile range: 0.8-1.5), nearly all had estrogen receptor positive disease (99%) and received hormone therapy (91%), and most underwent sentinel node biopsy (89%) with the remainder having no axillary surgery. At 530 person-years and a median follow-up of 39 months, 2 LRs were observed yielding a 48-month cumulative incidence of LR of 3.0% (95% CI: 0.56%-9.5%). Both events arose in patients with mixed lobular histology (none arose in patients with pure ILC). Two unrelated deaths were also observed yielding a 48-month OS of 98% (95% CI: 95%-100%)., Conclusion: Among patients with ILC who received APBI after breast conserving surgery, we observed a 4-year LR rate of 3%. No regional or distant recurrences were observed, and OS was excellent. The safety of APBI for ILC will require confirmation among larger trials with longer follow-up, although the excellent outcomes observed here are consistent with those seen for invasive ductal carcinomas among contemporary trials of APBI., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: Our purpose was to evaluate the measurement properties of patient-reported outcome (PRO) measures used in the ongoing RadComp pragmatic randomized clinical trial (PRCT)., Methods and Materials: The deidentified and blinded data set included 774 English-speaking female participants who completed their 6-month posttreatment assessment. Eleven PRO measures were evaluated, including the Trial Outcome Index from the Functional Assessment of Cancer Therapy-Breast (FACT-B), Satisfaction with Breast Cosmetic Outcomes, the BREAST-Q, and selected Patient-Reported Outcomes Measurement Information System (PROMIS) measures. PROs were measured at 3 timepoints: baseline, completion of radiation therapy (RT), and 6 months post-RT. Ten variables were used as validity anchors. Pearson or Spearman correlations were calculated between PROs and convergent validity indicators. Mean PRO differences between clinically distinct categories were compared with analysis of variance methods (known-groups validity). PRO change scores were mapped to change in other variables (sensitivity to change)., Results: Most correlations between PROs and validity indicators were large (≥0.5). Mean score for Satisfaction with Breast Cosmetic Outcomes was higher (better) for those with a lumpectomy compared with those with a mastectomy (P < .001). Mean scores for the FACT-B Trial Outcome Index and for PROMIS Fatigue and Ability to Participate in Social Roles and Activities were better for those with good baseline performance status compared with those with poorer baseline performance status (P < .05). At completion of RT and post-RT, mean scores for Satisfaction with Breast Cosmetic Outcomes and BREAST-Q Radiation were significantly different (P < .001) across categories for all Functional Assessment of Chronic Illness Therapy -Treatment Satisfaction - General items. There were medium-sized correlations between change scores for FACT-B Trial Outcome Index, Fatigue, Anxiety, and Ability to Participate in Social Roles and change scores in the Visual Analog Scale., Conclusions: For patients with nonmetastatic breast cancer receiving radiation in the RadComp PRCT, our findings demonstrate high reliability and validity for important PRO measures, supporting their psychometric strength and usefulness to reflect the effect of RT on health-related quality of life., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Regional nodal irradiation (RNI) for breast cancer yields improvements in disease outcomes, yet comprehensive target coverage often increases cardiac radiation therapy (RT) dose. Volumetric modulated arc therapy (VMAT) may mitigate high-dose cardiac exposure, although it often increases the volume of low-dose exposure. The cardiac implications of this dosimetric configuration (in contrast to historic 3D conformal techniques) remain uncertain., Methods and Materials: Eligible patients receiving adjuvant RNI using VMAT for locoregional breast cancer were prospectively enrolled in an IRB-approved study. Echocardiograms were performed prior to RT, at the conclusion of RT, and 6 months following RT. Echocardiographic parameters were measured by a single reader and measures were compared pre- and post-RT via the signed-rank test. Changes in echocardiographic parameters over time were compared to mean and max heart doses via the Spearman correlation test., Results: Among 19 evaluable patients (median age 38 years), 89% (n = 17) received doxorubicin and 37% (n = 7) received trastuzumab/pertuzumab combination therapy. All patients received VMAT-based whole-breast/chest wall and RNI. The average mean heart dose was 456 cGy (range, 187-697 cGy) and the average max heart dose was 3001 cGy (1560-4793 cGy). Among salient echocardiographic parameters, no significant decrement in cardiac function was observed when comparing pre-RT to 6 months post-RT: mean left ventricular ejection fraction (LVEF) was 61.8% (SD 4.4%) pre-RT and 62.7% (SD 3.8%) 6 months post-RT ( P = .493); mean global longitudinal strain (GLS) was -19.3% (SD 2.2%) pre-RT and -19.6% (SD 1.8%) 6 months post-RT ( P = .627). No individual patient exhibited reduced LVEF or sustained decrement in GLS. No correlations were observed for changes in LVEF or GLS when compared to mean or maximum heart doses ( P > .1 for all)., Conclusions: VMAT for left-sided RNI yielded no significant early decrement in echocardiographic parameters of cardiac function, including LVEF and GLS, within this limited cohort. No patient exhibited significant LVEF changes, and none exhibited sustained decrements in GLS. VMAT may be a reasonable approach to cardiac avoidance in patients requiring RNI, including those receiving anthracyclines and HER2-directed therapy. Larger cohorts with longer follow-ups will be needed to validate these findings., Competing Interests: The authors have no relevant conflicts of interest to disclose., (© 2024 The Author(s).)

Purpose: Intravascular tumor emboli in axillary soft tissue (ITE) is a rare pathologic finding in breast cancer and is associated with higher axillary nodal disease burden. The independent prognostic and predictive value of this entity is unknown, as is the role of radiation therapy for ITE., Methods and Materials: We analyzed a prospectively maintained database of breast cancer patients treated from 1992 to 2020. Patients with ITE were matched to those without (1:2) based on propensity scores to control for potential confounding factors. Locoregional (LRR) and distant recurrence (DR) were evaluated using competing risks methods accounting for death as a competing event. Overall survival (OS) and disease-free survival (DFS) were evaluated by Cox regression models. Among patients with ITE, we also evaluated whether RT improved outcomes., Results: Among 2377 total patients, 129 had ITE, of whom 126 were propensity score matched to 252 without ITE. Median follow-up from time of surgery was 5.5 years (IQR 2.3, 9.7). There were no statistically significant differences in the 5-year incidence of LRR between groups (5.4% [95% CI, 1.6%-13%] with ITE vs 10% [95% CI, 6.7%-15%] without, P = .53) or DR (24% [95% CI, 15% 35%] with ITE vs 21% [95% CI, 16%-27%] without, P = .51). Five-year OS and DFS did not differ between groups ( P > .9 for both comparisons, patients with ITE vs without ITE). In analyzing the effect of RT among patients with ITE, receipt of RT was associated with significantly improved DFS (HR, 0.34, 95% CI, 0.12-0.93, P = .04)., Conclusions: Patients with ITE do not exhibit significantly worse LRR, DR, DFS, or OS compared with a propensity-score-matched cohort without ITE. However, among patients with ITE, those who received RT demonstrated significantly improved DFS. Larger studies with longer follow-up are needed to evaluate the prognostic and predictive implications of ITE., (© 2024 The Author(s).)

Purpose: HER2-positive (HER2+) breast cancer historically exhibited the most adverse local outcomes and, consequently, has had limited representation among trials of partial breast irradiation (PBI). We hypothesized that with contemporary HER2-targeted agents, patients may now exhibit excellent disease control outcomes after adjuvant PBI., Methods and Materials: Using a prospectively maintained institutional database, we identified patients with HER2+ breast cancer treated with breast conserving surgery (BCS) and PBI from 2000 to 2022. Salient clinicopathologic and treatment parameters were collected. All patients received external beam PBI to 40 Gy in 10 daily fractions. Cumulative incidence functions were calculated to estimate the incidence of local recurrence (LR) with the competing risk of death., Results: We identified 1248 patients who underwent PBI at our institution, of whom the study cohort comprised 52 (4%) with HER2+ breast cancer (median age, 64 years; range, 44-87). Nearly all had T1 tumors (98%; median size, 12 mm [range, 1-21 mm]). Most had estrogen receptor positive disease (88%), and all patients had negative surgical margins. Nearly all underwent sentinel node biopsy (94%), with the remainder undergoing no surgical axillary evaluation. Forty-two (81%) received chemotherapy; 40 (77%), hormone therapy; and 42 (81%), HER2-directed therapy, most commonly trastuzumab. At 143.8 person-years of follow-up (range, 7-226 months for each patient), we observed 2 LR events at 14 and 26 months, respectively, yielding a 2-year LR rate of 3.8%. No regional or distant recurrences were observed, nor were any breast-specific mortality events. Two deaths were observed, both without evidence of disease., Conclusions: Among a cohort of patients with HER2+ early-stage breast cancer managed with BCS and PBI, we observed a 2-year LR rate of 3.8%, with no regional or distant recurrences and excellent overall survival. These findings require confirmation with longer follow-up among larger cohorts but appear consistent with the excellent results of contemporary randomized trials of PBI unselected for HER2 status., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Competing Interests: I declare no competing interests.

Radiotherapy is an integral component of multidisciplinary breast cancer care. Given how commonly radiotherapy is used in the treatment of breast cancer, many patients with recurrences have received previous radiotherapy. Patients with new primary breast cancer may also have received previous radiotherapy to the thoracic region. Curative doses and comprehensive field photon reirradiation (reRT) have often been avoided in these patients due to concerns for severe toxicities to organs-at-risk (OARs), such as the heart, lungs, brachial plexus, and soft tissue. However, many patients may benefit from definitive-intent reRT, such as patients with high-risk disease features such as lymph node involvement and dermal/epidermal invasion. Proton therapy is a potentially advantageous treatment option for delivery of reRT due to its lack of exit dose and greater conformality that allow for enhanced non-target tissue sparing of previously irradiated tissues. In this review, we discuss the clinical applications of proton therapy for patients with breast cancer requiring reRT, the currently available literature and how it compares to historical photon reRT outcomes, treatment planning considerations, and questions in this area warranting further study. Given the dosimetric advantages of protons and the data reported to date, proton therapy is a promising option for patients who would benefit from the added locoregional disease control provided by reRT for recurrent or new primary breast cancer.

Although adjuvant breast radiotherapy has long been a universal component of breast conservation therapy (BCT), it is now clear that "breast cancer" is a broad class of many disparate diseases with varying natural histories and risk profiles. In turn, some breast conservation patients enjoy exceedingly favorable outcomes following surgery alone. Ongoing trials seek to identify such low-risk patient populations, hypothesizing that some may safely forego radiotherapy. Whereas prior-generation trials focused on clinicopathologic features for risk stratification, contemporary studies are employing molecular biomarkers to identify those patients who are unlikely to benefit significantly from radiotherapy., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: Recurrent or new primary breast cancer requiring comprehensive regional nodal irradiation after prior radiation therapy (RT) to the supraclavicular area and upper axilla is challenging due to cumulative brachial plexus (BP) dose tolerance. We assessed BP dose sparing achieved with pencil beam scanning proton therapy (PBS-PT) and photon volumetric modulated arc therapy (VMAT)., Methods and Materials: In an institutional review board-approved planning study, all patients with ipsilateral recurrent breast cancer treated with PBS-PT re-RT (PBT1) with at least partial BP overlap from prior photon RT were identified. Comparative VMAT plans (XRT1) using matched BP dose constraints were developed. A second pair of proton (PBT2) and VMAT (XRT2) plans using standardized target volumes were created, applying uniform prescription dose of 50.4 per 1.8 Gy and a maximum BP constraint <25 Gy. Incidence of brachial plexopathy was also assessed., Results: Ten consecutive patients were identified. Median time between RT courses was 48 months (15-276). Median first, second, and cumulative RT doses were 50.4 Gy (range, 42.6-60.0), 50.4 Gy relative biologic effectiveness (RBE) (45.0-64.4), and 102.4 Gy (RBE) (95.0-120.0), respectively. Median follow-up was 15 months (5-33) and 18 months for living patients (11-33) Mean BP max was 37.5 Gy (RBE) for PBT1 and 36.9 Gy for XRT1. Target volume coverage of V85% (volume receiving 85% of prescription dose), V90%, and V95% were numerically lower for XRT1 versus PBT1. Similarly, axilla I-III and supraclavicular area coverage were significantly higher for PBT2 than XRT2 at dose levels of V55%, V65%, V75%, V85%, and V95%. Only axilla I V55% did not reach significance ( P = .06) favoring PBS-PT. Two patients with high cumulative BPmax (95.2 Gy [RBE], 101.6 Gy [RBE]) developed brachial plexopathy symptoms with ulnar nerve distribution neuropathy without pain or weakness (1 of 2 had symptom resolution after 6 months without intervention)., Conclusions: PBS-PT improved BP sparing and target volume coverage versus VMAT. For patients requiring comprehensive re-RT for high-risk, nonmetastatic breast cancer recurrence with BP overlap and reasonable expectation for prolonged life expectancy, PBT may be the preferred treatment modality., Competing Interests: J. Isabelle Choi reports personal fees from Varian Medical Systems outside of the scope of this work., (© 2023 The Author(s).)

Purpose: Metaplastic breast carcinoma (MBC) is a rare subtype of breast cancer, defined as mammary carcinoma with squamous or mesenchymal differentiation, that may include spindle cell, chondroid, osseous, or rhabdomyoid differentiation patterns. The implications of MBC recurrence and survival outcomes remains unclear., Methods: Cases were ascertained from a prospectively maintained institutional database of patients treated from 1998 to 2015. Patients with MBC were matched 1:1 to non-MBC cases. Cox proportional-hazards models and Kaplan-Meier estimates were used to evaluate outcome differences between cohorts., Results: 111 patients with MBC were matched 1:1 with non-MBC patients from an initial set of 2400 patients. Median follow-up time was 8 years. Most patients with MBC received chemotherapy (88%) and radiotherapy (71%). On univariate competing risk regression, MBC was not associated with locoregional recurrence (HR = 1.08; p = 0.8), distant recurrence (HR = 1.65; p = 0.092); disease-free survival (HR = 1.52; p = 0.065), or overall survival (HR = 1.56; p = 0.1). Absolute differences were noted in 8-year disease-free survival (49.6% MBC vs 66.4% non-MBC) and overall survival (61.3% MBC vs 74.4% non-MBC), though neither of these reached statistical significance (p = 0.07 and 0.11, respectively)., Conclusion: Appropriately-treated MBC may exhibit recurrence and survival outcomes that are difficult to distinguish from those of non-MBC. While prior studies suggest that MBC has a worse natural history than non-MBC triple-negative breast cancer, prudent use of chemotherapy and radiotherapy may narrow these differences, although studies with more power will be required to inform clinical management. Longer follow-up among larger populations may further elucidate the clinical and therapeutic implications of MBC., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Accelerated partial breast irradiation (APBI) after breast-conserving surgery offers a well-tolerated adjuvant radiation therapy option for patients with breast cancer. We sought to describe patient-reported acute toxicity as a function of salient dosimetric parameters during and after an APBI regimen of 40 Gy in 10 once-daily fractions., Methods and Materials: From June 2019 to July 2020, patients undergoing APBI were assigned a weekly, response-adapted, patient reported outcomes-common terminology criteria for adverse events-based acute toxicity assessment. Patients reported acute toxicity during treatment and for up to 8 weeks after treatment. Dosimetric treatment parameters were collected. Descriptive statistics and univariable analyses were used to summarize patient-reported outcomes and their correlation to corresponding dosimetric measures, respectively., Results: Overall, 55 patients who received APBI completed a total of 351 assessments. Median planning target volume was 210 cc (range, 64-580 cc), and median planning target volume:ipsilateral breast volume ratio was 0.17 (range, 0.05-0.44). Overall, 22% of patients reported moderate breast enlargement and 27% reported maximum skin toxicity as severe or very severe. Furthermore, 35% of patients reported fatigue, and 44% of patients reported pain in the radiated area as moderate to very severe. Median time to first report of any moderate to very severe symptom was 10 days (interquartile range, 6-27 days). By 8 weeks after APBI, most patients reported resolution of symptoms, with 16% reporting residual moderate symptoms. Upon univariable analysis, none of the ascertained salient dosimetric parameters were associated with maximum symptoms or with the presence of moderate to very severe toxicity., Conclusions: Weekly assessments during and after APBI showed that patients experienced moderate to very severe toxicities, most commonly skin toxicity, but that these typically resolved by 8 weeks after radiation therapy. More comprehensive evaluations among larger cohorts are warranted to define the precise dosimetric parameters that correspond to outcomes of interest., (© 2023 The Author(s).)

Purpose: Radiation therapy (RT) after breast-conserving surgery (BCS) for ductal carcinoma in situ (DCIS) reduces invasive and in situ recurrences. Whereas landmark studies suggest that a tumor bed boost improves local control for invasive breast cancer, the benefit in DCIS remains less certain. We evaluated outcomes of patients with DCIS treated with or without a boost., Methods and Materials: The study cohort comprised patients with DCIS who underwent BCS at our institution from 2004 to 2018. Clinicopathologic features, treatment parameters, and outcomes were ascertained from medical records. Patient and tumor characteristics were evaluated relative to outcomes using univariable and multivariable Cox models. Recurrence-free survival (RFS) estimates were generated using the Kaplan-Meier method., Results: We identified 1675 patients who underwent BCS for DCIS (median age, 56 years; interquartile range, 49-64 years). Boost RT was used in 1146 cases (68%) and hormone therapy in 536 (32%). At a median follow-up of 4.2 years (interquartile range, 1.4-7.0 years), we observed 61 locoregional recurrence events (56 local, 5 regional) and 21 deaths. Univariable logistic regression demonstrated that boost RT was more common among younger patients ( P < .001) with positive or close margins ( P < .001) and with larger tumors ( P < .001) of higher grade ( P  = .025). The 10-year RFS rate was 88.8% among those receiving a boost and 84.3% among those without a boost ( P  = .3), and neither univariable nor multivariable analyses revealed an association between boost RT and locoregional recurrence., Conclusions: Among patients with DCIS who underwent BCS, use of a tumor bed boost was not associated with locoregional recurrence or RFS. Despite a preponderance of adverse features among the boost cohort, outcomes were similar to those of patients not receiving a boost, suggesting that a boost may mitigate risk of recurrence among patients with high-risk features. Ongoing studies will elucidate the extent to which a tumor bed boost influences disease control rates., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Author(s).)

Purpose: The use of neoadjuvant chemotherapy (NAC) in patients with operable breast cancer allows for assessment of treatment response and subsequent tailoring of adjuvant therapy. Data are limited with respect to outcomes among patients with a heavy residual tumor burden after NAC. We report outcomes in patients who had exceptionally poor responses to NAC: those with >9 involved nodes after NAC or with 5 cm or more of residual disease in the breast., Methods and Materials: Between June 2014 and April 2020, 1511 patients with breast cancer received NAC followed by surgery at our institution. Poor responders, defined as those with positive nodes or residual tumor in the breast, were identified for analysis. Patients were further classified into 3 groups for comparison purposes: (1) 1 to 3 positive nodes; (2) 4 to 9 positive nodes; or (3) >9 positive nodes and/or >5 cm of residual tumor, which was defined as high-volume residual (HVR). Recurrence and survival outcomes were compared based on residual disease burden after NAC., Results: Among 934 poor responders, 539 patients had 1 to 3 positive nodes (ypN1), 215 had 4 to 9 positive nodes (ypN2), and 180 had HVR disease. Specifically, 118 had >9 positive nodes (HVR), and 62 patients had >5 cm of residual tumor in the breast. With a median follow-up of 31 months (interquartile range, 18-46), the 5-year overall survival rate was 88% among ypN1, 76% among ypN2, and 72% among patients with HVR disease (P < .001). The 5-year distant recurrence-free survival and locoregional recurrence incidences were 82% and 7.6% among ypN1 versus 67% and 8.4% among ypN2 versus 53% and 12% among HVR, respectively., Conclusions: Our work suggests that patients with HVR disease are at high risk for locoregional and distant recurrence as well as death, despite best available standard-of-care treatment. Intensification of locoregional therapies and/or alternative adjuvant systemic treatment may improve outcomes in these poor responders., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: Breast reirradiation (reRT) after breast conserving surgery (BCS) has emerged as a viable alternative to mastectomy for women presenting with recurrent or new primary breast cancer. There are limited data on safety of different fractionation regimens. This study reports safety and efficacy among women treated with repeat BCS and reRT., Methods and Materials: Patients who underwent repeat BCS followed by RT from 2015 to 2021 at 2 institutions were analyzed. Univariate logistic regression models were used to identify predictors of acute and late toxicities. Kaplan-Meier estimates were used to evaluate overall survival (OS), distant metastasis-free survival (DMFS) and locoregional recurrence-free survival (LR-RFS)., Results: Sixty-six patients were reviewed with median follow-up of 16 months (range: 3-60 months). At time of first recurrence, 41% had invasive carcinoma with a ductal carcinoma in situ (DCIS) component, 41% had invasive carcinoma alone and 18% had DCIS alone. All were clinically node negative. For the reirradiation course, 95% received partial breast irradiation (PBI) (57.5% with 1.5 Gy BID; 27% with 1.8 Gy daily; 10.5% with hypofractionation), and 5% received whole breast irradiation (1.8-2 Gy/fx), all of whom had received PBI for initial course. One patient experienced grade 3 fibrosis, and one patient experienced grade 3 telangiectasia. None had grade 4 or higher late adverse events. We found no association between the fractionation of the second course of RT or the cumulative dose (measured as EQD2) with acute or late toxicity. At 2 years, OS was 100%, DMFS was 91.6%, and LR-RFS was 100%., Conclusion: In this series of patients with recurrent or new primary breast cancer, a second breast conservation surgery followed by reirradiation was effective with no local recurrences and an acceptable toxicity profile across a range of available fractionation regimens at a median follow up of 16 months. Longer follow up is required., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Skin tattoos represent the standard approach for surface alignment and setup of breast cancer radiation therapy, yet permanent skin markings contribute to adverse cosmesis and patient dissatisfaction. With the advent of contemporary surface-imaging technology, we evaluated setup accuracy and timing between "tattoo-less" and traditional tattoo-based setup techniques., Methods and Materials: Patients receiving accelerated partial breast irradiation (APBI) underwent traditional tattoo-based setup (TTB), alternating daily with a tattoo-less setup via surface imaging using AlignRT (ART). Following initial setup, position was verified via daily kV imaging, with matching on surgical clips representing ground truth. Translational shifts (TS) and rotational shifts (RS) were ascertained, as were setup time and total in-room time. Statistical analyses used the Wilcoxon signed rank test and Pitman-Morgan variance test., Results: A total of 43 patients receiving APBI and 356 treatment fractions were analyzed (174 TTB fractions and 182 using ART). For tattoo-less setup via ART, the median absolute TS were 0.31 cm in the vertical (range, 0.08-0.82), 0.23 cm in the lateral (0.05-0.86), and 0.26 cm in the longitudinal (0.02-0.72) axes. For TTB setup, the corresponding median TS were 0.34 cm (0.05-1.98), 0.31 cm (0.09-1.84), and 0.34 cm (0.08-1.25), respectively. The median magnitude shifts were 0.59 (0.30-1.31) for ART and 0.80 (0.27-2.13) for TTB. ART was not statistically distinguishable from TTB in terms of TS, except in the longitudinal direction ( P  = .154, .059, and .021, respectively), and was superior to TTB for magnitude shift ( P < .001). The variance of each TS variable was significantly narrower for ART compared with TTB ( P ≤ .001 vertical, P  = .001 lateral, P  = .005 longitudinal). The median absolute RS for ART was 0.64° rotation (range, 0.00-1.90), 0.65° roll (0.05-2.90), and 0.30° pitch (0.00-1.50). The corresponding median RS for TTB were 0.80° (0.00-2.50), 0.64° (0.00-3.00), and 0.46° (0.00-2.90), respectively. ART setup was not statistically different from TTB in terms of RS ( P  = .868, .236, and .079, respectively). ART showed lower variance than TTB in terms of pitch ( P  = .009). The median total in-room time was shorter for ART than TTB (15.42 vs 17.25 minutes; P  = .008), as was the median setup time (11.12 vs 13.00 minutes; P  = .001). Moreover, ART had a narrower distribution of setup time with fewer lengthy outliers versus TTB., Conclusions: These findings suggest that a tattoo-less setup approach with AlignRT may be sufficiently accurate and expeditious to supplant surface tattoos for patients receiving APBI. Further analyses with larger cohorts will determine whether tattoo-based approaches can be replaced by noninvasive surface imaging., (© 2023 The Author(s).)

Purpose: : Guidelines for early-stage breast cancer allow for radiation therapy (RT) omission after breast conserving surgery among older women, though high utilization of RT persists. This study explored surgeon referral and the effect of a productivity-based bonus metric for radiation oncologists in an academic institution with centralized quality assurance review., Methods and Materials: : We evaluated patients ≥70 years of age treated with breast conserving surgery for estrogen receptor (ER)+ pT1N0 breast cancer at a single tertiary cancer network between 2015 and 2018. The primary outcomes were radiation oncology referral and RT receipt. Covariables included patient and physician characteristics and treatment decisions before versus after productivity metric implementation. Univariable generalized linear effects models explored associations between these outcomes and covariables., Results: : Of 703 patients included, 483 (69%) were referred to radiation oncology and 273 (39%) received RT (among those referred, 57% received RT). No difference in RT receipt pre- versus post-productivity metric implementation was observed ( P  = .57). RT receipt was associated with younger patient age (70-74 years; odds ratio [OR], 2.66; 95% confidence interval [CI], 1.54-4.57) and higher grade (grade 3; OR, 7.75; 95% CI, 3.33-18.07). Initial referral was associated with younger age (70-74; OR, 5.64; 95% CI, 3.37-0.45) and higher performance status (Karnofsky performance status ≥90; OR, 5.34; 95% CI, 2.63-10.83)., Conclusions: : Nonreferral to radiation oncology accounted for half of RT omission but was based on age and Karnofsky performance status, in accordance with guidelines. Lack of radiation oncologist practice change in response to misaligned financial incentives is reassuring, potentially reflecting incentive design and/or centralized quality assurance review. Multi-institutional studies are needed to confirm these findings., (© 2022 The Authors.)

Purpose: Evidence suggests that cancer treatment-related toxic effects are underreported by clinicians. We sought to compare patient- and clinician-reported acute toxic effects among patients undergoing radiation therapy for primary breast cancer and to determine factors associated with patient-clinician discordance., Methods and Materials: Patient responses from a weekly Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events based assessment were matched to clinician assessments of acute toxic effects during treatment. Weighted κ statistics were used to evaluate agreement between patient and clinician assessments. Linear regression, logistic regression, and generalized estimating equation models were used to identify covariates associated with discordance., Results: Overall, 842 patient-clinician assessment pairs from 376 unique patients were analyzed. Total symptom burden score was higher for patients than clinicians (4.7 vs 2.3, P < .01). Dermatitis, pruritis, pain, and edema items were classified as having minimal agreement (κ of 0.25, 0.23, 0.20, and 0.25, respectively). Fatigue (κ 0.17) and psychosocial (0.03) patient-clinician pairs were found to have no agreement. The linear regression demonstrated that assessments by patients who identified as Black or African American were associated with a 0.13-point decrease in discordance (95% confidence interval, -0.25 to -0.01), while time from the start of treatment was associated with increased discordance (95% confidence interval, 0.07-0.12)., Conclusions: For patients undergoing breast radiation therapy, discordance in patient and clinician symptom reporting is high and increases as treatment progresses. The mechanism of reduced discordance among Black or African American patients warrants further investigation. Prospective studies are needed to determine whether interventions for lower severity symptoms, which are commonly overlooked by clinicians, can reduce symptom burden and improve patient quality of life during radiation therapy., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: The RxPONDER trial reported no benefit to chemotherapy among postmenopausal patients with HR + /HER2 - tumors, one to three positive nodes, and low recurrence scores, questioning the role of axillary staging in this population. Here, we evaluate the impact of sentinel lymph node biopsy (SLNB) results on adjuvant therapy decisions in postmenopausal women with HR + /HER2 - breast cancer., Patients and Methods: Postmenopausal women with cT1-2N0, HR + /HER2 - breast cancer treated with lumpectomy and SLNB from 2012 to 2018 were identified. Receipt of nodal irradiation, indication for axillary lymph node dissection (ALND) and chemotherapy, and partial breast irradiation (PBI) eligibility were reviewed with pre- and post-SLNB results., Results: A total of 1786 women were identified: median age 62 years, 84% with pT1 tumors, and 16% with pT2-3 tumors. Of those, 85% (n = 1525) remained pN0, 14% (n = 244) were pN1, and 1% (n = 17) were pN2-3. A total of 20 (1%) patients had > 2 positive SLNs, necessitating ALND. Pre-SLNB, 1478 women were considered PBI eligible; post-SLNB, 227 (13%) converted to PBI ineligible. In total, 58 patients with positive nodes received nodal irradiation, representing 3% of the entire cohort and 22% of pN+ patients. Overall, 1401 patients had an Oncotype DX recurrence score available, including 1273 patients with pN0 stage and 128 with pN1, with 173 (14%) and 16 (13%), respectively, having a recurrence score > 25, warranting chemotherapy., Conclusions: While few cN0 postmenopausal women with HR + /HER2 - tumors had nodal pathology that warranted ALND, receipt of nodal irradiation, or indicated need for chemotherapy, in 13%, SLNB would have an impact on consideration for PBI. Among patients eligible for PBI, findings from SLNB may help refine selection among postmenopausal women with this tumor profile., (© 2022. Society of Surgical Oncology.)

Historically, axillary lymph node dissection was considered necessary for regional control of breast cancer. Moreover, nodal status was the major determinant of the need for chemotherapy. The increased use of systemic therapy coupled with expanding indications for nodal irradiation has led to interest in optimizing patient outcomes by leveraging the local control benefits of radiotherapy and systemic therapy to decrease the extent of surgery. A series of landmark surgical and radiotherapeutic trials has demonstrated low rates of disease recurrence with concomitant improvements in treatment-associated lymphedema and quality of life with the use of sentinel node biopsy and nodal irradiation as opposed to complete axillary dissection in the management of node positive breast cancer. This chapter will explore the evolution of regional nodal management, culminating in current approaches to tailored patient selection for axillary lymph node dissection, sentinel lymph node biopsy, and adjuvant regional nodal irradiation., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: Dosimetric and technical challenges often limit radiation therapy (RT) target coverage for patients with breast cancer who require bilateral breast/chest wall and regional nodal irradiation (RNI). We evaluated the feasibility of using volumetric modulated arc therapy (VMAT) to administer bilateral comprehensive RNI including the internal mammary nodes., Methods and Materials: We analyzed all patients treated at our institution with bilateral RNI using VMAT between 2017 and 2020. Medical records were reviewed to ascertain clinicopathologic features, radiotherapeutic parameters, and treatment-related adverse events., Results: The cohort was comprised of 12 patients who underwent VMAT for bilateral RNI, with a median follow-up time of 14.5 months. Median volume of the lung receiving 5 Gy (V 5 ) for the bilateral lungs was 96.1% (range, 84.5%-99.8%), and median volume of the lung receiving 20 Gy for each lung was 27.5% (range, 14.9%-38.1%). The cardiac mean dose was a median of 699 cGy (range, 527-1117 cGy). Five patients (41%) developed grade 1 cough/dyspnea, with one patient developing grade 3 dyspnea. Of note, 3 of these patients (60%) were current or former smokers. No patient received glucocorticoid therapy or required respiratory intervention, and none developed longer-term pulmonary complaints. A decline in ejection fraction occurred in one patient with a preexisting cardiac condition who also received anthracycline-based chemotherapy and trastuzumab. Only one patient experienced a locoregional recurrence with synchronous distant progression, and subsequently succumbed to the disease. No secondary cancers have been noted to date., Conclusions: VMAT appears to be a feasible and tolerable RT modality for patients with breast cancer who require bilateral comprehensive adjuvant RT with RNI to obtain excellent target coverage. No patients required medical intervention for pulmonary complaints despite a median bilateral V 5 approaching 100%, providing further evidence that V 5 is not predictive for complications., (Copyright © 2021 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: Late local recurrences and second primary breast cancers are increasingly common. Proton beam therapy (PBT) reirradiation (reRT) may allow safer delivery of a second definitive radiotherapy (RT) course. We analyzed outcomes of patients with recurrent or new primary breast cancer who underwent reRT., Materials and Methods: In an IRB-approved retrospective study, patient/tumor characteristics, treatment parameters, outcomes, and toxicities were collected for all consecutive patients with recurrent or new primary non-metastatic breast cancer previously treated with breast or chest wall RT who underwent PBT reRT., Results: Forty-six patients received reRT using uniform (70%) or pencil beam (30%) scanning PBT. Median first RT, reRT, and cumulative doses were 60 Gy (range 45-66 Gy), 50.4 Gy(RBE) (40-66.6 Gy(RBE)), and 110 Gy(RBE) (96.6-169.4 Gy(RBE)), respectively. Median follow-up was 21 months. There were no local or regional recurrences; 17% developed distant recurrence. Two-year DMFS and OS were 92.0% and 93.6%, respectively. Nine of 13 (69.2%) patients who underwent implant or flap reconstruction developed capsular contracture, 3 (23.1%) requiring surgical intervention. One (7.7%) patient developed grade 3 breast pain requiring mastectomy after breast conserving surgery. No acute or late grade 4-5 toxicities were seen. Increased body mass index (BMI) was protective of grade ≥ 2 acute toxicity (OR = 0.84, 95%CI = 0.70-1.00)., Conclusion: In the largest series to date of PBT reRT for breast cancer recurrence or new primary after prior definitive breast or chest wall RT, excellent locoregional control and few high-grade toxicities were encountered. PBT reRT may provide a relatively safe and highly effective salvage option. Additional patients and follow-up are needed to correlate composite normal tissue doses with toxicities and assess long-term outcomes., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Purpose: We aimed to develop and study the implementation of a remote system for toxicity assessment and management of acute side effects of breast radiation using electronic patient-reported outcomes (ePROs)., Methods and Materials: A response-adapted Patient-Reported Outcomes Common Terminology Criteria for Adverse Events-based assessment for breast radiation toxicity was administered weekly during and for 8 weeks after radiation from June 2019 to July 2020. The care team received alerts when "severe" symptoms were reported by patients, who were then contacted. Treatment, clinic, and sociodemographic characteristics were abstracted from patient records. A subsample of patients and care team members was qualitatively interviewed at follow-up., Results: Overall, 5787 assessments were sent to 678 patients, of whom 489 (72%) completed 2607 assessments (45%). Moderate or greater toxicity was reported by 419 responders (86%; 95% CI, 82%-89%). Clinician alerts for severe toxicity were generated for 264 assessments among 139 unique patients, of which 83% occurred posttreatment. The proportion of surveys that prompted an alert was significantly higher after treatment (219 [13%]) than during treatment (45 [5%]) (P < .001). Survey completion rates in the posttreatment period were higher among patients undergoing partial breast irradiation than postmastectomy radiation (incidence rate ratio, 0.70; 95% CI, 0.60-0.81) (P < .001) despite these patients experiencing less severe toxicity. Interviews (15) found that patients had a positive experience with ePROs, although many thought the primary purpose was for research rather than symptom management., Conclusions: With the majority of toxicity occurring after breast radiation has ended, remote symptom monitoring with ePROs appears to fill a gap in clinical practice, particularly for patients undergoing shorter courses of radiation. It is important to properly onboard patients and explain that the purpose of ePROs is to aid clinical care. Further research is needed to determine whether the costs associated with ePROs can be offset by reducing routine clinic visits and whether this approach is acceptable and appropriate., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Acquired somatic mutations in hematopoietic stem and progenitor cells (clonal hematopoiesis or CH) are associated with advanced age, increased risk of cardiovascular and malignant diseases, and decreased overall survival. These adverse sequelae may be mediated by altered inflammatory profiles observed in patients with CH. A pro-inflammatory immunologic profile is also associated with worse outcomes of certain infections, including SARS-CoV-2 and its associated disease Covid-19. Whether CH predisposes to severe Covid-19 or other infections is unknown. Among 525 individuals with Covid-19 from Memorial Sloan Kettering (MSK) and the Korean Clonal Hematopoiesis (KoCH) consortia, we show that CH is associated with severe Covid-19 outcomes (OR = 1.85, 95%=1.15-2.99, p = 0.01), in particular CH characterized by non-cancer driver mutations (OR = 2.01, 95% CI = 1.15-3.50, p = 0.01). We further explore the relationship between CH and risk of other infections in 14,211 solid tumor patients at MSK. CH is significantly associated with risk of Clostridium Difficile (HR = 2.01, 95% CI: 1.22-3.30, p = 6×10 -3 ) and Streptococcus/Enterococcus infections (HR = 1.56, 95% CI = 1.15-2.13, p = 5×10 -3 ). These findings suggest a relationship between CH and risk of severe infections that warrants further investigation., (© 2021. The Author(s).)

Purpose: Mastectomy has long been the preferred approach for local salvage of recurrent breast cancer following breast-conservation therapy (BCT). Growing interest in avoiding mastectomy prompted RTOG 1014, a landmark phase two study demonstrating the feasibility of repeat BCT using a novel radiotherapy (RT) regimen (i.e., 45 Gy administered in 30 fractions of 1.5 Gy twice-daily to the partial breast, "rePBI"). We adopted this regimen as our institutional standard and report our observations regarding the safety and efficacy of rePBI as salvage therapy., Methods: All patients at our institution who underwent repeat BCT and subsequently received rePBI from 2011 to 2019 were identified. Clinicopathologic features and treatment characteristics for both primary breast cancers and recurrences were collected, as were rates of subsequent recurrence and treatment-associated toxicities., Results: The cohort included 34 patients with a median age of 65.8 (46.2-78.2) at the time of rePBI. At a median follow-up of 23.5 months, there were two subsequent locoregional recurrences (2-year local control rate 97%). There was no grade ≥ 3 toxicity. The most common acute toxicity (< 3 months) was radiation dermatitis (100%), and common grade 1-2 late toxicities (> 3 months) included fibrosis in 14 (41%), breast asymmetry in 12 (35%), and chest wall pain in 11 (32%)., Conclusions: Repeat breast conservation using the hyperfractionated partial breast RT regimen defined by RTOG 1014 (45 Gy administered in 30 1.5 Gy twice-daily fractions) appears effective and well tolerated. No grade 3 or higher toxicities were observed and local control was excellent. Longer term follow-up among larger cohorts will define whether salvage mastectomy should remain the preferred standard.

Perineural invasion (PNI) is a pathologic finding observed across a spectrum of solid tumors, typically with adverse prognostic implications. Little is known about how the presence of PNI influences locoregional recurrence (LRR) among breast cancers. We evaluated the association between PNI and LRR among an unselected, broadly representative cohort of breast cancer patients, and among a propensity-score matched cohort. We ascertained breast cancer patients seen at our institution from 2008 to 2019 for whom PNI status and salient clinicopathologic features were available. Fine-Gray regression models were constructed to evaluate the association between PNI and LRR, accounting for age, tumor size, nodal involvement, estrogen receptor (ER), progesterone receptor (PR), HER2 status, histologic tumor grade, presence of lymphovascular invasion (LVI), and receipt of chemotherapy and/or radiation. Analyses were then refined by comparing PNI-positive patients to a PNI-negative cohort defined by propensity score matching. Among 8864 invasive breast cancers, 1384 (15.6%) were noted to harbor PNI. At a median follow-up of 6.3 years, 428 locoregional recurrence events were observed yielding a 7-year LRR of 7.1% (95% CI 5.5-9.1) for those with PNI and 4.7% (95% CI 4.2-5.3; p = 0.01) for those without. On univariate analysis throughout the entire cohort, presence of PNI was significantly associated with an increased risk of LRR (HR 1.39, 95% CI 1.08-1.78, p < 0.01). Accounting for differences in salient clinicopathologic and treatment parameters by multivariable Fine-Gray regression modeling, the association between PNI and LRR was potentiated (HR 1.57, 95% CI 1.2-2.07, p = 0.001). We further conducted propensity score matching to balance clinicopathologic parameters and treatments between the two groups (PNI vs not), again showing a similar significant association between PNI and LRR (HR 1.46, 95% CI 1.03-2.08, p = 0.034). PNI is significantly associated with LRR following the definitive treatment of invasive breast cancer. The excess risk conferred by PNI is similar in magnitude to that observed with LVI, or by ER/PR negativity. Breast cancer prognostication and therapeutic decision-making should consider the presence of PNI among other salient risk factors. Larger studies among more uniform breast cancer presentations may elucidate the extent to which these findings apply across breast cancer subtypes and stages.

Background: For patients with breast cancer undergoing breast-conserving surgery (BCS), adjuvant radiation (RT) and hormonal therapy (HT) reduce the risk of locoregional recurrence (LRR). Although several studies have evaluated adjuvant HT ± RT, the outcomes of HT versus RT monotherapy remain less clear. In this study, the risk of LRR is characterized among older patients with early-stage breast cancer following adjuvant RT alone, HT alone, neither, or both., Methods: This study included female patients from the Memorial Sloan Kettering Cancer Center (New York, New York) who were aged ≥65 years with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) T1N0 breast cancer treated with BCS. The primary endpoint was time to LRR evaluated by Cox regression analysis., Results: There were 888 women evaluated with a median age of 71 years (range, 65-100 years) and median follow-up of 4.9 years (range, 0.0-9.5 years). There were 27 LRR events (3.0%). Five-year LRR was 11% for those receiving no adjuvant treatment, 3% for HT alone, 4% for RT alone, and 1% for HT and RT. LRR rates were significantly different between the groups (P < .001). Compared with neither HT nor RT, HT or RT monotherapy each yielded similar LRR reductions: HT alone (HR, 0.27; 95% CI, 0.10-0.68; P = .006) and RT alone (HR, 0.32; 95% CI, 0.11-0.92; P = .034). Distant recurrence and breast cancer-specific survival rates did not significantly differ between groups., Conclusions: LRR risk following BCS is low among women aged ≥65 years with T1N0, ER+/HER2- breast cancer. Adjuvant RT and HT monotherapy each similarly reduce this risk; the combination yields a marginal improvement. Further study is needed to elucidate whether appropriate patients may feasibly receive adjuvant RT monotherapy versus the current standards of HT monotherapy or combined RT/HT., (© 2021 American Cancer Society.)

Background: Breast conservation therapy (BCT) is well established for the management of primary operable breast cancer, with oncologic outcomes comparable to those of mastectomy. It remains unclear whether re-conservation therapy (RCT) is suitable for those patients who develop ipsilateral breast tumor recurrence (IBTR), for whom mastectomy is generally recommended., Methods: We identified women who underwent BCT for invasive or ductal carcinoma in situ and developed IBTR as a first event, comparing the pattern of subsequent events and survival for those treated by RCT versus mastectomy., Results: Of 16,968 patents who had BCT, 322 (1.9%) developed an isolated IBTR as a first event between 1999 and 2019. 130 (40%) had RCT and 192 (60%) mastectomy. Compared to mastectomy, the RCT patients were older (66 vs 53, < 0.001), had a longer disease-free interval (DFI: 5.8 vs 2.7 years (p < 0.001)), were less likely to have received RT (p < 0.001), endocrine therapy (ET) (p < 0.005) or combined RT/ET (< 0.001) as initial treatment, but the characteristics of their initial primary cancers and of their IBTR were comparable. At a median follow-up of 10.7 years following initial BCT and 6.5 years following IBTR, there were no differences in BCSS or OS between RCT and mastectomy., Conclusion: For BCT patients who developed IBTR as a first event, we observed comparable BCSS and OS from time of initial treatment and from time of IBTR, whether treated by RCT or mastectomy. These results support wider consideration of RCT in the management of IBTR, especially in the setting of older age and longer DFI.

Purpose: Breast cancer diagnosis at a very young age has been independently correlated with worse outcomes. Appropriately intensifying treatment in these patients is warranted, even as we acknowledge the risks of potentially mutagenic adjuvant therapies. We examined local control, distant control, overall survival, and secondary malignancy rates by age cohort and by initial surgical strategy., Methods and Materials: Female patients less than or equal to 35 years of age diagnosed with invasive breast cancer from January 1, 1990, to December 31, 2010, were identified. Control groups of those aged 36 to 50 years (n = 6246) and 51 to 70 years (n = 7294) were delineated from an institutional registry. Clinicopathologic and follow-up information was collected. Chi-squared test was used to compare frequencies of categorical variables. Survival endpoints were evaluated using Kaplan-Meier methodology., Results: A total of 529 patients ≤35 years of age met criteria for analysis. The median age of diagnosis was 32 years (range 20-35). Median follow-up was 10.3 years. On multivariable analysis, factors associated with overall survival (OS) were tumor size (hazard ratio [HR] 1.14, P = .02), presence of lymphovascular invasion (HR 2.2, P <.001), estrogen receptor positivity (HR 0.64, P = .015), receipt of adjuvant chemotherapy (HR 0.52, P = .035), and black race (HR 2.87, P <.001). The ultra-young were more likely to experience local failure compared with the aged 36 to 50 group (HR 2.2, 95% CI 1.8-2.6, P < .001) and aged 51 to 70 group (HR 3.1, 95% CI 2.45 - 3.9, P <.001). The cumulative incidence of secondary malignancies at 5 and 10 years was 2.2% and 4.4%, respectively. Receipt of radiation was not significantly associated with secondary malignancies or contralateral breast cancer., Conclusion: Survival and recurrence outcomes in breast cancer patients ≤35 years are worse compared with those aged 36 to 50 or 51 to 70 years. Based on our data, breast conservation therapy is appropriate for these patients, and the concern for second malignancies should not impinge on the known indications for postoperative radiation therapy., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Radiation therapy is one of the most commonly used cancer therapeutics but genetic determinants of clinical benefit are poorly characterized. Pathogenic germline variants in ATM are known to cause ataxia-telangiectasia, a rare hereditary syndrome notable for marked radiosensitivity. In contrast, somatic inactivation of ATM is a common event in a wide variety of cancers, but its clinical actionability remains obscure., Methods: We analyzed 20 107 consecutively treated advanced cancer patients who underwent targeted genomic sequencing as part of an institutional genomic profiling initiative and identified 1085 harboring a somatic or germline ATM mutation, including 357 who received radiotherapy (RT). Outcomes of irradiated tumors harboring ATM loss-of-function (LoF) mutations were compared with those harboring variants of unknown significance. All statistical tests were 2-sided., Results: Among 357 pan-cancer patients who received 727 courses of RT, genetic inactivation of ATM was associated with improved radiotherapeutic efficacy. The 2-year cumulative incidence of irradiated tumor progression was 13.2% vs 27.5% for tumors harboring an ATM LoF vs variant of unknown significance allele, respectively (hazard ratio [HR] = 0.51, 95% confidence interval [CI] = 0.34 to 0.77, P = .001). The greatest clinical benefit was seen in tumors harboring biallelic ATM inactivation (HR = 0.19, 95% CI = 0.06 to 0.60, P = .005), with statistically significant benefit also observed in tumors with monoallelic ATM inactivation (HR = 0.57, 95% CI = 0.35 to 0.92, P = .02). Notably, ATM LoF was highly predictive of outcome in TP53 wild-type tumors but not among TP53-mutant tumors., Conclusions: We demonstrate that somatic ATM inactivation is associated with markedly improved tumor control following RT. The identification of a radio-sensitive tumor phenotype across multiple cancer types offers potential clinical opportunities for genomically guided RT., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

ATM , a gene that controls repair of DNA double-strand breaks, confers an excess lifetime risk of breast cancer among carriers of germline pathogenic variants (PV). ATM PV homozygotes are particularly sensitive to DNA damage caused by ionizing radiation. Consequently, there is concern that adjuvant radiotherapy (RT) may cause excess morbidity among heterozygous carriers of ATM PV. We evaluated the tolerability of breast RT among carriers of ATM germline variants., Methods: Of 167 patients with ATM germline variants presenting to our institution with breast cancer, 91 received RT. Treatment-related toxicity was ascertained from medical records and graded across organ systems. Toxicities grade > 2 were recorded from the end of treatment to last evaluable follow-up and were analyzed according to ATM variant pathogenicity., Results: Of 91 evaluable carriers of ATM variants, with a median follow-up of 32 months following RT, 25% (n = 23) harbored a PV, whereas 75% (n = 68) harbored a variant of uncertain significance (VUS). Prevalence of grade ≥ 2 toxicity unrelated to post-mastectomy reconstruction among patients with ATM PV was: 32% at the end of treatment ( v 34% for VUS carriers), 11% at 1 year of follow-up ( v 4% for VUS carriers), and 8% at the last follow-up ( v 13% for VUS carriers), consistent with previous studies of RT among unselected populations. No grade 4 or 5 toxicities were observed. ATM variant pathogenicity was not associated with local toxicity, contralateral breast cancer, or secondary malignancy in this limited cohort of patients who received breast RT., Conclusion: We found no evidence of excess RT-associated toxicity among carriers of pathogenic ATM germline variants. Breast-conserving therapy and adjuvant RT may be safely considered among appropriately selected carriers of ATM germline variants., (© 2021 by American Society of Clinical Oncology.)

Stably acquired mutations in hematopoietic cells represent substrates of selection that may lead to clonal hematopoiesis (CH), a common state in cancer patients that is associated with a heightened risk of leukemia development. Owing to technical and sample size limitations, most CH studies have characterized gene mutations or mosaic chromosomal alterations (mCAs) individually. Here we leverage peripheral blood sequencing data from 32,442 cancer patients to jointly characterize gene mutations (n = 14,789) and mCAs (n = 383) in CH. Recurrent composite genotypes resembling known genetic interactions in leukemia genomes underlie 23% of all detected autosomal alterations, indicating that these selection mechanisms are operative early in clonal evolution. CH with composite genotypes defines a patient group at high risk of leukemia progression (3-year cumulative incidence 14.6%, CI: 7-22%). Multivariable analysis identifies mCA as an independent risk factor for leukemia development (HR = 14, 95% CI: 6-33, P < 0.001). Our results suggest that mCA should be considered in conjunction with gene mutations in the surveillance of patients at risk of hematologic neoplasms.

Importance: After neoadjuvant chemotherapy (NAC), pathologic complete response (pCR) is an optimal outcome and a surrogate end point for improved disease-free and overall survival. To date, surgical resection remains the only reliable method for diagnosing pCR., Objective: To evaluate the accuracy of magnetic resonance imaging (MRI)-guided biopsy for diagnosing a pCR after NAC compared with reference-standard surgical resection., Design, Setting, and Participants: Single-arm, phase 1, nonrandomized controlled trial in a single tertiary care cancer center from September 26, 2017, to July 29, 2019. The median follow-up was 1.26 years (interquartile range, 0.85-1.59 years). Data analysis was performed in November 2019. Eligible patients had (1) stage IA to IIIC biopsy-proven operable invasive breast cancer; (2) standard-of-care NAC; (3) MRI before and after NAC, with imaging complete response defined as no residual enhancement on post-NAC MRI; and (4) definitive surgery. Patients were excluded if they were younger than 18 years, had a medical reason precluding study participation, or had a prior history of breast cancer., Interventions: Post-NAC MRI-guided biopsy without the use of intravenous contrast of the tumor bed before definitive surgery., Main Outcomes and Measures: The primary end point was the negative predictive value of MRI-guided biopsy, with true-negative defined as negative results of the biopsy (ie, no residual cancer) corresponding to a surgical pCR. Accuracy, sensitivity, positive predictive value, and specificity were also calculated. Two clinical definitions of pCR were independently evaluated: definition 1 was no residual invasive cancer; definition 2, no residual invasive or in situ cancer., Results: Twenty of 23 patients (87%) had evaluable data (median [interquartile range] age, 51.5 [39.0-57.5] years; 20 women [100%]; 13 White patients [65%]). Of the 20 patients, pre-NAC median tumor size on MRI was 3.0 cm (interquartile range, 2.0-5.0 cm). Nineteen of 20 patients (95%) had invasive ductal carcinoma; 15 of 20 (75%) had stage II cancer; 11 of 20 (55%) had ERBB2 (formerly HER2 or HER2/neu)-positive cancer; and 6 of 20 (30%) had triple-negative cancer. Surgical pathology demonstrated a pCR in 13 of 20 (65%) patients and no pCR in 7 of 20 patients (35%) when pCR definition 1 was used. Results of MRI-guided biopsy had a negative predictive value of 92.8% (95% CI, 66.2%-99.8%), with accuracy of 95% (95% CI, 75.1%-99.9%), sensitivity of 85.8% (95% CI, 42.0%-99.6%), positive predictive value of 100%, and specificity of 100% for pCR definition 1. Only 1 patient had a false-negative MRI-guided biopsy result (surgical pathology showed <0.02 cm of residual invasive cancer)., Conclusions and Relevance: This study's results suggest that the accuracy of MRI-guided biopsy to diagnose a post-NAC pCR approaches that of reference-standard surgical resection. MRI-guided biopsy may be a viable alternative to surgical resection for this population after NAC, which supports the need for further investigation., Trial Registration: ClinicalTrials.gov Identifier: NCT03289195.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) novel coronavirus 2019 (COVID-19) global pandemic has led to millions of cases and hundreds of thousands of deaths. While older adults appear at high risk for severe disease, hospitalizations and deaths due to SARS-CoV-2 among children have been relatively rare. Integrating single-cell RNA sequencing (scRNA-seq) of developing mouse lung with temporally resolved immunofluorescence in mouse and human lung tissue, we found that expression of SARS-CoV-2 Spike protein primer TMPRSS2 was highest in ciliated cells and type I alveolar epithelial cells (AT1), and TMPRSS2 expression increased with aging in mice and humans. Analysis of autopsy tissue from fatal COVID-19 cases detected SARS-CoV-2 RNA most frequently in ciliated and secretory cells in airway epithelium and AT1 cells in peripheral lung. SARS-CoV-2 RNA was highly colocalized in cells expressing TMPRSS2. Together, these data demonstrate the cellular spectrum infected by SARS-CoV-2 in lung epithelium and suggest that developmental regulation of TMPRSS2 may underlie the relative protection of infants and children from severe respiratory illness.

Clonal hematopoiesis (CH) occurs when blood cells harboring an advantageous mutation propagate faster than others. These mutations confer a risk for hematological cancers and cardiovascular disease. Here, we analyze CH in blood samples from a pair of twin astronauts over 4 years in bulk and fractionated cell populations using a targeted CH panel, linked-read whole-genome sequencing, and deep RNA sequencing. We show CH with distinct mutational profiles and increasing allelic fraction that includes a high-risk, TET2 clone in one subject and two DNMT3A mutations on distinct alleles in the other twin. These astronauts exhibit CH almost two decades prior to the mean age at which it is typically detected and show larger shifts in clone size than age-matched controls or radiotherapy patients, based on a longitudinal cohort of 157 cancer patients. As such, longitudinal monitoring of CH may serve as an important metric for overall cancer and cardiovascular risk in astronauts., Competing Interests: Declaration of Interests No relevant conflicts apply to this work, but C.E.M. is a cofounder of Onegevity and Biotia. D.H. and C.E.M. also have positions at Tempus Labs., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Acquired somatic mutations in hematopoietic stem and progenitor cells (clonal hematopoiesis or CH) are associated with advanced age, increased risk of cardiovascular and malignant diseases, and decreased overall survival. 1-4 These adverse sequelae may be mediated by altered inflammatory profiles observed in patients with CH. 2,5,6 A pro-inflammatory immunologic profile is also associated with worse outcomes of certain infections, including SARS-CoV-2 and its associated disease Covid-19. 7,8 Whether CH predisposes to severe Covid-19 or other infections is unknown. Among 515 individuals with Covid-19 from Memorial Sloan Kettering (MSK) and the Korean Clonal Hematopoiesis (KoCH) consortia, we found that CH was associated with severe Covid-19 outcomes (OR=1.9, 95%=1.2-2.9, p=0.01). We further explored the relationship between CH and risk of other infections in 14,211 solid tumor patients at MSK. CH was significantly associated with risk of Clostridium Difficile (HR=2.0, 95% CI: 1.2-3.3, p=6×10 -3 ) and Streptococcus/Enterococcus infections (HR=1.5, 95% CI=1.1-2.1, p=5×10 -3 ). These findings suggest a relationship between CH and risk of severe infections that warrants further investigation.

Purpose: Our purpose was to present and evaluate expert consensus on contouring primary breast tumors on magnetic resonance imaging (MRI) in the setting of neoadjuvant partial breast irradiation in trials., Methods and Materials: Expert consensus on contouring guidelines for target definition of primary breast tumors on contrast-enhanced MRI in trials was developed by an international team of experienced breast radiation oncologists and a dedicated breast radiologist during 3 meetings. At the first meeting, draft guidelines were developed through discussing and contouring 2 cases. At the second meeting 6 breast radiation oncologists delineated gross tumor volume (GTV) in 10 patients with early-stage breast cancer (cT1N0) according to draft guidelines. GTV was expanded isotropically (20 mm) to generate clinical target volume (CTV), excluding skin and chest wall. Delineations were reviewed for disagreement and guidelines were clarified accordingly. At the third meeting 5 radiation oncologists redelineated 6 cases using consensus-based guidelines. Interobserver variation of GTV and CTV was assessed using generalized conformity index (CI). CI was calculated as the sum of volumes each pair of observers agreed upon, divided by the sum of encompassing volumes for each pair of observers., Results: For the 2 delineation sessions combined, mean GTV ranged between 0.19 and 2.44 cm 3 , CI for GTV ranged between 0.28 and 0.77, and CI for CTV between 0.77 and 0.94. The largest interobserver variation in GTV delineations was observed in cases with extended tumor spiculae, blood vessels near or markers within the tumor, or with increased enhancement of glandular breast tissue. Consensus-based guidelines stated to delineate all visible tumors on contrast enhanced-MRI scan 1 to 2 minutes after contrast injection and if a marker was inserted in the tumor to include this., Conclusions: Expert-based consensus on contouring primary breast tumors on MRI in trials has been reached. This resulted in low interobserver variation for CTV in the context of a uniform 20 mm GTV to CTV expansion margin., (Copyright © 2020 American Society for Radiation Oncology. All rights reserved.)

Importance: Regional nodal irradiation (RNI) for node-positive breast cancer reduces distant metastases and improves survival, albeit with limited reduction in regional nodal recurrences. The mechanism by which RNI robustly reduces distant metastases while modestly influencing nodal recurrences (ie, the presumed target of RNI) remains unclear., Objective: To determine whether some distant metastases putatively arise from occult regional nodal disease and whether regional recurrences otherwise remain largely undetected until an advanced cancer presentation., Design, Setting, and Participants: This cohort study examined patients presenting with de novo stage IV breast cancer to the Memorial Sloan Kettering Cancer Center in New York, New York, from 2006 to 2018. Medical records were reviewed to ascertain clinicopathological parameters, including estrogen receptor status and survival. Pretreatment positron emission tomography-computed tomography (PET-CT) imaging was reviewed to ascertain the extent of regional nodal involvement at metastatic diagnosis using standard nodal assessment criteria. A subset underwent regional lymph node biopsy for diagnostic confirmation and served to validate the radiographic nodal assessment. Data analysis was performed from October 2019 to February 2020., Exposures: Untreated metastatic breast cancer., Main Outcome and Measures: The primary outcome was the likelihood of regional nodal involvement at the time of metastatic breast cancer presentation and was determined by reviewing pretreatment PET-CT imaging and lymph node biopsy findings., Results: Among 597 women (median [interquartile range] age, 53 [44-65] years) with untreated metastatic breast cancer, 512 (85.8%) exhibited regional lymph node involvement by PET-CT or nodal biopsy, 509 (85%) had involvement of axillary level I, 328 (55%) had involvement in axillary level II, 136 (23%) had involvement in axillary level III, 101 (17%) had involvement in the supraclavicular fossa, and 96 (16%) had involvement in the internal mammary chain. Lymph node involvement was more prevalent among estrogen receptor-negative tumors (92.4%) than estrogen receptor-positive tumors (83.6%). Nodal involvement at the time of metastatic diagnosis was not associated with overall survival., Conclusions and Relevance: These findings suggest that a majority of patients with de novo metastatic breast cancer harbor regional lymph node disease at presentation, consistent with the hypothesis that regional involvement may precede metastatic dissemination. This is in alignment with the findings of landmark trials suggesting that RNI reduces distant recurrences. It is possible that this distant effect of RNI may act via eradication of occult regional disease prior to systemic seeding. The challenges inherent in detecting isolated nodal disease (which is typically asymptomatic) may account for the more modest observed benefit of RNI on regional recurrences. Alternative explanations of nodal involvement that arises concurrently or after metastatic dissemination remain possible, but do not otherwise explain the association of RNI with distant recurrence.