The presence of extensive lymphovascular invasion (LVI) is associated with higher risks of local-regional recurrence compared to usual LVI in curatively treated breast cancer patients.

PURPOSE/OBJECTIVES: Several datasets have demonstrated a correlation between lymph-vascular invasion (LVI) and local-regional 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 (non-extensive) LVI (LVI) and 4) extensive LVI (E-LVI). MATERIALS/METHODS: Between 12/2009 and 8/2021, 8837 patients with early-stage breast cancer were treated with curative intent and were evaluable. Clinical-pathological 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 vs. E-LVI. RESULTS: Of the 8837 patients studied, 5584 were neg, 461 had FS-LVI, 2315 had LVI, and 477 had E-LVI. Patient with E-LVI had an adverse risk profile compared to the other groups. The 5- and 10-year local regional recurrence (LRR) cumulative incidence estimates in patients with E-LVI were 9.6% (95% CI: 7.1-13) and 13% (95% CI: 10-17), which were significantly higher than 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 on univariable (HR 1.4, 95% CI [1.03-1.89], p-value 0.029) and multivariable regression analysis (HR 1.62, 95% CI [1.15-2.27], p-value 0.005) when compared to non-extensive LVI. In an alternative approach, we performed a 2:1 propensity-matched analysis comparing LVI to E-LVI patients. The hazard ratio for LRR (HR 1.47 (CI 1.02-2.14, p=0.041) was suggestive of a higher risk 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 PMRT, the finding of E-LVI might be decisive in favor of intensified treatment.

Validation of Patient-Reported Outcomes in Patients With Nonmetastatic Breast Cancer Receiving Comprehensive Nodal Irradiation in the RadComp Trial.

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.

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.

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.

Proton Reirradiation for High-Risk Recurrent or New Primary Breast Cancer.

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.

Incorporating Tumor Biology to Select Patients for the Omission of Radiation Therapy.

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.

Accelerated Partial Breast Irradiation: Association of Dosimetric Parameters With Patient-Reported Outcomes.

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.

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.

Early effectiveness and toxicity outcomes of reirradiation after breast conserving surgery for recurrent or new primary breast cancer.

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.

The Effect of Surgeon Referral and a Radiation Oncologist Productivity-Based Metric on Radiation Therapy Receipt Among Elderly Women With Early Stage Breast Cancer: Analysis From a Tertiary Cancer Network.

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.

Outcomes of Breast Cancer Patients with High Volume of Residual Disease Following Neoadjuvant Chemotherapy.

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.

How Often Do Sentinel Lymph Node Biopsy Results Affect Adjuvant Therapy Decisions Among Postmenopausal Women with Early-Stage HR+/HER2- Breast Cancer in the Post-RxPONDER Era?

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.

Regional Nodal Management in the Setting of Up-Front Surgery.

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.

A Comparison of Patient- and Clinician-Reported Acute Toxic Effects During Radiation Therapy for Primary Breast Cancer.

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.