Breast Cancer Presenting With Intravascular Tumor Emboli in Axillary Soft Tissue: Recurrence Risk and Radiation Therapy Outcomes.

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.

40 Gray in 5 Fractions for Salvage Reirradiation of Spine Lesions Previously Treated With Stereotactic Body Radiotherapy.

BACKGROUND AND PURPOSE: A retrospective single-center analysis of the safety and efficacy of reirradiation to 40 Gy in 5 fractions (reSBRT) in patients previously treated with stereotactic body radiotherapy to the spine was performed. METHODS: We identified 102 consecutive patients treated with reSBRT for 105 lesions between 3/2013 and 8/2021. Sixty-three patients (61.8%) were treated to the same vertebral level, and 39 (38.2%) to overlapping immediately adjacent levels. Local control was defined as the absence of progression within the treated target volume. The probability of local progression was estimated using a cumulative incidence curve. Death without local progression was considered a competing risk. RESULTS: Most patients had extensive metastatic disease (54.9%) and were treated to the thoracic spine (53.8%). The most common regimen in the first course of stereotactic body radiotherapy was 27 Gy in 3 fractions, and the median time to reSBRT was 16.4 months. At the time of simulation, 44% of lesions had advanced epidural disease. Accordingly, 80% had myelogram simulations. Both the vertebral body and posterior elements were treated in 86% of lesions. At a median follow-up time of 13.2 months, local failure occurred in 10 lesions (9.5%). The 6- and 12-month cumulative incidences of local failure were 4.8% and 6%, respectively. Seven patients developed radiation-related neuropathy, and 1 patient developed myelopathy. The vertebral compression fracture rate was 16.7%. CONCLUSION: In patients with extensive disease involvement, reSBRT of spine metastases with 40 Gy in 5 fractions seems to be safe and effective. Prospective trials are needed to determine the optimal dose and fractionation in this clinical scenario.

Comparative Evaluation of Proton Therapy and Volumetric Modulated Arc Therapy for Brachial Plexus Sparing in the Comprehensive Reirradiation of High-Risk Recurrent Breast Cancer.

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.

Accelerated Partial Breast Irradiation for HER2-Positive Early-Stage Breast Cancer.

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.

Stereotactic Body Radiation Therapy for Stage IIA to IIIA Inoperable Non-Small Cell Lung Cancer: A Phase 1 Dose-Escalation Trial.

PURPOSE: Larger tumors are underrepresented in most prospective trials on stereotactic body radiation therapy (SBRT) for inoperable non-small cell lung cancer (NSCLC). We performed this phase 1 trial to specifically study the maximum tolerated dose (MTD) of SBRT for NSCLC >3 cm. METHODS AND MATERIALS: A 3 + 3 dose-escalation design (cohort A) with an expansion cohort at the MTD (cohort B) was used. Patients with inoperable NSCLC >3 cm (T2-4) were eligible. Select ipsilateral hilar and single-station mediastinal nodes were permitted. The initial SBRT dose was 40 Gy in 5 fractions, with planned escalation to 50 and 60 Gy in 5 fractions. Adjuvant chemotherapy was mandatory for cohort A and optional for cohort B, but no patients in cohort B received chemotherapy. The primary endpoint was SBRT-related acute grade (G) 4+ or persistent G3 toxicities (Common Terminology Criteria for Adverse Events version 4.03). Secondary endpoints included local failure (LF), distant metastases, disease progression, and overall survival. RESULTS: The median age was 80 years; tumor size was >3 cm and ≤5 cm in 20 (59%) and >5 cm in 14 patients (41%). In cohort A (n = 9), 3 patients treated to 50 Gy experienced G3 radiation pneumonitis (RP), thus defining the MTD. In the larger dose-expansion cohort B (n = 25), no radiation therapy-related G4+ toxicities and no G3 RP occurred; only 2 patients experienced G2 RP. The 2-year cumulative incidence of LF was 20.2%, distant failure was 34.7%, and disease progression was 54.4%. Two-year overall survival was 53%. A biologically effective dose (BED) <100 Gy was associated with higher LF (P = .006); advanced stage and higher neutrophil/lymphocyte ratio were associated with greater disease progression (both P = .004). CONCLUSIONS: Fifty Gy in 5 fractions is the MTD for SBRT to tumors >3 cm. A higher BED is associated with fewer LFs even in larger tumors. Cohort B appears to have had less toxicity, possibly due to the omission of chemotherapy.

Genomic analysis and clinical correlations of non-small cell lung cancer brain metastasis.

Up to 50% of patients with non-small cell lung cancer (NSCLC) develop brain metastasis (BM), yet the study of BM genomics has been limited by tissue access, incomplete clinical data, and a lack of comparison with paired extracranial specimens. Here we report a cohort of 233 patients with resected and sequenced (MSK-IMPACT) NSCLC BM and comprehensive clinical data. With matched samples (47 primary tumor, 42 extracranial metastatic), we show CDKN2A/B deletions and cell cycle pathway alterations to be enriched in the BM samples. Meaningful clinico-genomic correlations are noted, namely EGFR alterations in leptomeningeal disease (LMD) and MYC amplifications in multifocal regional brain progression. Patients who developed early LMD frequently have had uncommon, multiple, and persistently detectable EGFR driver mutations. The distinct mutational patterns identified in BM specimens compared to other tissue sites suggest specific biologic underpinnings of intracranial progression.

Locoregional Control Benefit of a Tumor Bed Boost for Ductal Carcinoma In Situ.

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.

Accuracy and Efficiency of Patient Setup Using Surface Imaging versus Skin Tattoos for Accelerated Partial Breast Irradiation.

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.

Metaplastic carcinoma of the breast: matched cohort analysis of recurrence and survival.

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.

Evidence-based region of interest (ROI) definition for surface-guided radiotherapy (SGRT) of abdominal cancers using deep-inspiration breath-hold (DIBH).

To define and evaluate the appropriate abdominal region of interest (ROI) as a surrogate of diaphragm positioning in deep-inspiration breath-hold (DIBH) for surface-guided radiotherapy (SGRT) of abdominal cancers using 3D optical surface imaging (OSI). Six potential abdominal ROIs were evaluated to calculate their correlations with the diaphragm position using 4DCT images of 20 abdominal patients. Twelve points of interest (POIs) were defined (six on the central soft tissue and six on the bilateral ribs) at three superior-inferior levels, and different sub-groups represented different ROIs. ROI-1 was the largest, containing all 12 POIs from the xiphoid to the umbilicus and between the lateral body midlines while ROI-2 had only eight inferior POIs, ROI-3 had six lateral POIs, and ROI-4 had four superior-lateral POIs over the ribs, ROI-5 contained six central and two most inferior-lateral POIs and ROI-6 contained six central and four inferior-lateral POIs. Internally, the right diaphragm dome was used to represent its positions in 4DCT (0% and 50% within the cycle). The Pearson correlation coefficients were calculated between the diaphragm dome and all 12 external POIs individually or grouped as six ROIs. The quality of the abdominal ROIs was evaluated as potential internal surrogates and, therefore, potential ROIs for SGRT DIBH setup. The four most inferior POIs show the highest mean correlation (r = 0.75) with diaphragmatic motion, and the correlation decreases as POIs move superiorly. The mean correlations are the highest for ROIs with little or no rib support: r = 0.67 for ROI-2, r = 0.64 for ROI-5, and r = 0.63 for ROI-6, while lower for ROIs with rib support: ROI-1 has r = 0.60, ROI-3 has r = 0.50, and ROI-4 has only r = 0.28. This study demonstrates that the rectangular/triangular soft-tissue ROI (with little rib support) is an optimal surrogate for body positioning and diaphragmatic motion, even when treating tumors under the rib cage. This evidence-based ROI definition should be utilized when treating abdominal cancers with free-breathing (FB) and/or DIBH setup.

Bilateral Regional Nodal Irradiation Using Volumetric Modulated Arc Therapy: Dosimetric Analysis and Feasibility.

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 (V5) 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 V5 approaching 100%, providing further evidence that V5 is not predictive for complications.

Tolerability of Breast Radiotherapy Among Carriers of ATM Germline Variants.

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.

Perineural invasion as a risk factor for locoregional recurrence of invasive breast cancer.

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.

Salvage of locally recurrent breast cancer with repeat breast conservation using 45 Gy hyperfractionated partial breast re-irradiation.

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.

Breast conservation among older patients with early-stage breast cancer: Locoregional recurrence following adjuvant radiation or hormonal therapy.

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.

Regional Lymph Node Involvement Among Patients With De Novo Metastatic Breast Cancer.

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.

Breast Radiation Therapy Under COVID-19 Pandemic Resource Constraints-Approaches to Defer or Shorten Treatment From a Comprehensive Cancer Center in the United States.

PURPOSE: Breast radiation therapy accounts for a significant proportion of patient volume in contemporary radiation oncology practice. In the setting of anticipated resource constraints and widespread community infection with SARS-CoV-2 during the COVID-19 pandemic, measures for balancing both infectious and oncologic risk among patients and providers must be carefully considered. Here, we present evidence-based guidelines for omitting or abbreviating breast cancer radiation therapy, where appropriate, in an effort to mitigate risk to patients and optimize resource utilization. METHODS AND MATERIALS: Multidisciplinary breast cancer experts at a high-volume comprehensive cancer center convened contingency planning meetings over the early days of the COVID-19 pandemic to review the relevant literature and establish recommendations for the application of hypofractionated and abbreviated breast radiation regimens. RESULTS: Substantial evidence exists to support omitting radiation among certain favorable risk subgroups of patients with breast cancer and for abbreviating or accelerating regimens among others. For those who require either whole-breast or postmastectomy radiation, with or without coverage of the regional lymph nodes, a growing body of literature supports various hypofractionated approaches that appear safe and effective. CONCLUSIONS: In the setting of a public health emergency with the potential to strain critical healthcare resources and place patients at risk of infection, the parsimonious application of breast radiation therapy may alleviate a significant clinical burden without compromising long-term oncologic outcomes. The judicious and personalized use of immature study data may be warranted in the setting of a competing mortality risk from this widespread pandemic.

Patterns of Recurrence Among Higher-Risk Patients Receiving Daily External Beam Accelerated Partial-Breast Irradiation to 40 Gy in 10 Fractions.

PURPOSE: The 2016 American Society for Radiation Oncology consensus guidelines for the use of accelerated partial-breast irradiation (APBI) define "suitable," "cautionary," and "unsuitable" populations for this adjuvant breast radiation therapy technique. We sought to determine whether patients in the cautionary group exhibited adverse outcomes after APBI compared with their suitable counterparts. METHODS AND MATERIALS: We identified 252 consecutively treated patients from a single institution with in situ or early-stage invasive breast cancer who underwent APBI between 2008 and 2017. Treatment technique was uniform throughout the population, consisting of 3-dimensional conformal radiation therapy to 40 Gy administered in 10 daily fractions. RESULTS: One hundred seventy-eight patients (70%) were classified as suitable, 69 (27%) as cautionary, and 5 (2.0%) as unsuitable. Because unsuitable patients were few and had no recurrences, they were excluded from analysis. At a median follow-up time of 3.9 years, 97.2% of patients were free of recurrence. Four patients (1.5% overall; 3 suitable and 1 cautionary) experienced ipsilateral in-breast recurrences, and 1 cautionary patient developed an ipsilateral regional recurrence in an axillary lymph node. There was no significant difference in the rate of ipsilateral breast recurrence (2.4% vs 1.0%) between cautionary and suitable groups. CONCLUSIONS: Local recurrences are rare among guideline-defined cautionary patients with in situ or invasive breast cancer treated with APBI delivered via daily 3-dimensional conformal radiation therapy to 40 Gy. At a median follow-up of 3.9 years, no significant differences in local control were noted between cautionary and suitable patient groups. Further study is needed to characterize long-term disease outcomes among various risk groups.

The effects of the orthopedic metal artifact reduction (O-MAR) algorithm on contouring and dosimetry of head and neck radiotherapy patients.

Metallic objects, such as dental fillings, cause artifacts in computed tomography (CT) scans. We quantify the contouring and dosimetric effects of Orthopedic Metal Artifact Reduction (O-MAR), in head and neck radiotherapy. The ease of organ contouring was assessed by having a radiation oncologist identify the CT data set with or without O-MAR for each of 28 patients that was easier to contour. The effect on contouring was quantified further by having the physician recontour parotid glands, previously drawn by him on the O-MAR scans, on uncorrected scans, and calculating the Dice coefficent (a measure of overlap) for the contours. Radiotherapy plans originally generated on scans reconstructed with O-MAR were recalculated on scans without metal artifact correction. The study was done using the Analytical Anisotropic Algorithm (AAA) dose calculation algorithm. The 15 patients with a planning target volume (PTV) extending to the same slice as the artifacts were used for this part of the study. The normal tissue doses were not significantly affected. The PTV mean dose and V95 were not affected, but the cold spots became less severe in the O-MAR corrected plans, with the minimum point dose on average being 4.1% higher. In 79% of the cases, the radiation oncologist identified the O-MAR scan as easier to contour; in 11% he chose the uncorrected scan and in 11% the scans were judged to have equal quality. A total of nine parotid glands (on both scans-18 contours in total) in 5 patients were recontoured. The average Dice coefficient for parotids drawn with and without O-MAR was found to be 0.775 +/- 0.045. The O-MAR algorithm does not produce a significant dosimetric effect in head and neck plans when using the AAA dose calculation algorithm. It can therefore be used for improved contouring accuracy without updating the critical structure tolerance doses and target coverage expectations.

Long-Term Pulmonary Outcomes of a Feasibility Study of Inverse-Planned, Multibeam Intensity Modulated Radiation Therapy in Node-Positive Breast Cancer Patients Receiving Regional Nodal Irradiation.

PURPOSE: Multibeam intensity modulated radiation therapy (IMRT) enhances the therapeutic index by increasing the dosimetric coverage of the targeted tumor tissues while minimizing volumes of adjacent organs receiving high doses of RT. The tradeoff is that a greater volume of lung is exposed to low doses of RT, raising concern about the risk of radiation pneumonitis (RP). METHODS AND MATERIALS: Between July 2010 and January 2013, patients with node-positive breast cancer received inverse-planned, multibeam IMRT to the breast or chest wall and regional nodes, including the internal mammary nodes (IMNs). The primary endpoint was feasibility, predefined by dosimetric treatment planning criteria. Secondary endpoints included the incidence of RP grade 3 or greater and changes in pulmonary function measured with the Common Terminology Criteria for Adverse Events version 3.0 scales, pulmonary function tests and community-acquired pneumonia questionnaires, obtained at baseline and 6 months after IMRT. Clinical follow-up was every 6 months for up to 5 years. RESULTS: Median follow-up was 53.4 months (range, 0-82 months). Of 113 patients enrolled, 104 completed follow-up procedures. Coverage of the breast or chest wall and IMN was comprehensive (median 48.1 Gy and 48.9 Gy, respectively). The median volume of lung receiving a high dose (V20Gy) and a low dose (V5) was 29% and 100%, respectively. The overall rate of respiratory toxicities was 10.6% (11/104), including 1 grade 3 RP event (0.96%). No differences were found in pulmonary function test or community-acquired pneumonia scores after IMRT. The 5-year rates of locoregional recurrence-free, disease-free, and overall survival were 93.2%, 63.6%, and 80.3%, respectively. CONCLUSIONS: Multibeam IMRT in patients with breast cancer receiving regional nodal irradiation was dosimetrically feasible, based on early treatment planning criteria. Despite the large volume of lung receiving low-dose RT, the incidence of grade 3 RP was remarkably low, justifying inverse-planned IMRT as a treatment modality for patients with high-risk breast cancer in whom conventional RT techniques prove inadequate.