Post-mastectomy radiation therapy after breast reconstruction: from historic dogmas to practical expert agreements based on a large literature review of surgical and radiation therapy considerations.

Breast reconstruction (BR) after mastectomy is important to consider for a woman's body image enhancement and psychological well-being. Although post-mastectomy radiation (PMRT) significantly improves the outcome of patients with high-risk breast cancer (BC), PMRT after BR may affect cosmetic outcomes and may compromise the original goal of improving quality of life (QoL). With the lack of practical guidelines, it seems essential to work on a consensus and provide some "expert agreements" to offer patients the best option for PMRT after BR. We report a global "expert agreement" that results from a critical review of the literature on BR and PMRT during the 6th international multidisciplinary breast conference in March 2023.

The Presence of Extensive Lymphovascular Invasion is Associated With Higher Risks of Local-Regional Recurrence Compared With Usual Lymphovascular Invasion in Curatively Treated Breast Cancer Patients.

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.

Omission of Radiotherapy After Breast-Conserving Surgery for Women With Breast Cancer With Low Clinical and Genomic Risk: 5-Year Outcomes of IDEA.

PURPOSE: Multiple studies have shown a low risk of ipsilateral breast events (IBEs) or other recurrences for selected patients age 65-70 years or older with stage I breast cancers treated with breast-conserving surgery (BCS) and endocrine therapy (ET) without adjuvant radiotherapy. We sought to evaluate whether younger postmenopausal patients could also be successfully treated without radiation therapy, adding a genomic assay to classic selection factors. METHODS: Postmenopausal patients age 50-69 years with pT1N0 unifocal invasive breast cancer with margins ≥2 mm after BCS whose tumors were estrogen receptor-positive, progesterone receptor-positive, and human epidermal growth factor receptor 2-negative with Oncotype DX 21-gene recurrence score ≤18 were prospectively enrolled in a single-arm trial of radiotherapy omission if they consented to take at least 5 years of ET. The primary end point was the rate of locoregional recurrence 5 years after BCS. RESULTS: Between June 2015 and October 2018, 200 eligible patients were enrolled. Among the 186 patients with clinical follow-up of at least 56 months, overall and breast cancer-specific survival rates at 5 years were both 100%. The 5-year freedom from any recurrence was 99% (95% CI, 96 to 100). Crude rates of IBEs for the entire follow-up period for patients age 50-59 years and age 60-69 years were 3.3% (2/60) and 3.6% (5/140), respectively; crude rates of overall recurrence were 5.0% (3/60) and 3.6% (5/140), respectively. CONCLUSION: This trial achieved a very low risk of recurrence using a genomic assay in combination with classic clinical and biologic features for treatment selection, including postmenopausal patients younger than 60 years. Long-term follow-up of this trial and others will help determine whether the option of avoiding initial radiotherapy can be offered to a broader group of women than current guidelines recommend.

Patient-Reported Outcomes in Patients Undergoing Lumpectomy With and Without Defect Closure.

BACKGROUND: The effect of lumpectomy defect repair (a level 1 oncoplastic technique) on patient-reported breast satisfaction among patients undergoing lumpectomy has not yet been investigated. METHODS: Patients undergoing lumpectomy at our institution between 2018 and 2020 with or without repair of their lumpectomy defect during index operation, comprised our study population. The BREAST-Q quality-of-life questionnaire was administered preoperatively, and at 6 months, 1 year, and 2 years postoperatively. Satisfaction and quality-of-life domains were compared between those who did and did not have closure of their lumpectomy defect, and compared with surgeon-reported outcomes. RESULTS: A total of 487 patients met eligibility criteria, 206 (42%) had their partial mastectomy defect repaired by glandular displacement. Median breast volume, as calculated from the mammogram, was smaller in patients undergoing defect closure (826 cm3 vs. 895 cm3, p = 0.006). There were no statistically significant differences in satisfaction with breasts (SABTR), physical well-being of the chest (PWB-CHEST), or psychosocial well-being (PsychWB) scores between the two cohorts at any time point. While patients undergoing defect closure had significantly higher sexual well-being (SexWB) scores compared with no closure (66 vs. 59, p = 0.021), there were no predictors of improvement in SexWB scores over time on multivariable analysis. Patients' self-reported scores positively correlated with physician-reported outcomes. CONCLUSIONS: Despite a larger lumpectomy-to-breast volume ratio among patients undergoing defect repair, satisfaction was equivalent among those whose defects were or were not repaired at 2 years postsurgery. Defect repair was associated with clinically relevant improvement in patient-reported sexual well-being.

Use of a supervised machine learning model to predict Oncotype DX risk category in node-positive patients older than 50 years of age.

PURPOSE: The use of the Oncotype DX recurrence score (RS) to predict chemotherapy benefit in patients with hormone receptor-positive/HER2 negative (HR+/HER2-) breast cancer has recently expanded to include postmenopausal patients with N1 disease. RS availability is limited in resource-poor settings, however, prompting the development of statistical models that predict RS using clinicopathologic features. We sought to assess the performance of our supervised machine learning model in a cohort of patients > 50 years of age with N1 disease. METHODS: We identified patients > 50 years of age with pT1-2N1 HR+/HER2- breast cancer and applied the statistical model previously developed in a node-negative cohort, which uses age, pathologic tumor size, histology, progesterone receptor expression, lymphovascular invasion, and tumor grade to predict RS. We measured the model's ability to predict RS risk category (low: RS ≤ 25; high: RS > 25). RESULTS: Our cohort included 401 patients, 60.6% of whom had macrometastases, with a median of 1 positive node. The majority of patients had a low-risk observed RS (85.8%). For predicting RS category, the model had specificity of 97.3%, sensitivity of 31.8%, a negative predictive value of 87.9%, and a positive predictive value of 70.0%. CONCLUSION: Our model, developed in a cohort of node-negative patients, was highly specific for identifying cN1 patients > 50 years of age with a low RS who could safely avoid chemotherapy. The use of this model for identifying patients in whom genomic testing is unnecessary would help decrease the cost burden in resource-poor settings as reliance on RS for adjuvant treatment recommendations increases.

A multi-institutional prediction model to estimate the risk of recurrence and mortality after mastectomy for T1-2N1 breast cancer.

BACKGROUND: Post-mastectomy radiation therapy (PMRT) in women with pathologic stage T1-2N1M0 breast cancer is controversial. METHODS: Data from five North American institutions including women undergoing mastectomy without neoadjuvant therapy with pT1-2N1M0 breast cancer treated from 2006 to 2015 were pooled for analysis. Competing-risks regression was performed to identify factors associated with locoregional recurrence (LRR), distant metastasis (DM), overall recurrence (OR), and breast cancer mortality (BCM). RESULTS: A total of 3532 patients were included for analysis with a median follow-up time among survivors of 6.8 years (interquartile range [IQR], 4.5-9.5 years). The 2154 (61%) patients who received PMRT had significantly more adverse risk factors than those patients not receiving PMRT: younger age, larger tumors, more positive lymph nodes, lymphovascular invasion, extracapsular extension, and positive margins (p < .05 for all). On competing risk regression analysis, receipt of PMRT was significantly associated with a decreased risk of LRR (hazard ratio [HR], 0.21; 95% confidence interval [CI], 0.14-0.31; p < .001) and OR (HR, 0.76; 95% CI, 0.62-0.94; p = .011). Model performance metrics for each end point showed good discrimination and calibration. An online prediction model to estimate predicted risks for each outcome based on individual patient and tumor characteristics was created from the model. CONCLUSIONS: In a large multi-institutional cohort of patients, PMRT for T1-2N1 breast cancer was associated with a significant reduction in locoregional and overall recurrence after accounting for known prognostic factors. An online calculator was developed to aid in personalized decision-making regarding PMRT in this population.

Supervised machine learning model to predict oncotype DX risk category in patients over age 50.

PURPOSE: Routine use of the oncotype DX recurrence score (RS) in patients with early-stage, estrogen receptor-positive, HER2-negative (ER+/HER2-) breast cancer is limited internationally by cost and availability. We created a supervised machine learning model using clinicopathologic variables to predict RS risk category in patients aged over 50 years. METHODS: From January 2012 to December 2018, we identified patients aged over 50 years with T1-2, ER+/HER2-, node-negative tumors. Clinicopathologic data and RS results were randomly split into training and validation cohorts. A random forest model with 500 trees was developed on the training cohort, using age, pathologic tumor size, histology, progesterone receptor (PR) expression, lymphovascular invasion (LVI), and grade as predictors. We predicted risk category (low: RS ≤ 25, high: RS > 25) using the validation cohort. RESULTS: Of the 3880 tumors identified, 1293 tumors comprised the validation cohort in patients of median (IQR) age 62 years (56-68) with median (IQR) tumor size 1.2 cm (0.8-1.7). Most tumors were invasive ductal (80.3%) of low-intermediate grade (80.5%) without LVI (80.9%). PR expression was ≤ 20% in 27.3% of tumors. Specificity for identifying RS ≤ 25 was 96.3% (95% CI 95.0-97.4) and the negative predictive value was 92.9% (95% CI 91.2-94.4). Sensitivity and positive predictive value for predicting RS > 25 was lower (48.3 and 65.1%, respectively). CONCLUSION: Our model was highly specific for identifying eligible patients aged over 50 years for whom chemotherapy can be omitted. Following external validation, it may be used to triage patients for RS testing, if predicted to be high risk, in resource-limited settings.

Nodal Recurrence in Patients With Node-Positive Breast Cancer Treated With Sentinel Node Biopsy Alone After Neoadjuvant Chemotherapy-A Rare Event.

IMPORTANCE: Prospective trials have demonstrated sentinel lymph node (SLN) false-negative rates of less than 10% when 3 or more SLNs are retrieved in patients with clinically node-positive breast cancer rendered clinically node-negative with neoadjuvant chemotherapy (NAC). However, rates of nodal recurrence in such patients treated with SLN biopsy (SLNB) alone are unknown because axillary lymph node dissection (ALND) was performed in all patients, limiting adoption of this approach. OBJECTIVE: To evaluate nodal recurrence rates in a consecutive cohort of patients with clinically node-positive (cN1) breast cancer receiving NAC, followed by a negative SLNB using a standardized technique, and no further axillary surgery. DESIGN, SETTING, AND PARTICIPANTS: From November 2013 to February 2019, a cohort of consecutively identified patients with cT1 to cT3 biopsy-proven N1 breast cancer rendered cN0 by NAC underwent SLNB with dual tracer mapping and omission of ALND if 3 or more SLNs were identified and all were pathologically negative. Metastatic nodes were not routinely clipped, and localization of clipped nodes was not performed. The study was performed in a single tertiary cancer center. INTERVENTION: Omission of ALND in patients with cN1 breast cancer after NAC if 3 or more SLNs were pathologically negative. MAIN OUTCOME AND MEASURES: The primary outcome was the rate of nodal recurrence among patients with cN1 breast cancer treated with SLNB alone after NAC. RESULTS: Of 610 patients with cN1 breast cancer treated with NAC, 555 (91%) converted to cN0 and underwent SLNB; 234 (42%) had 3 or more negative SLNs and had SLNB alone. The median (IQR) age of these 234 patients was 49 (40-58) years; median tumor size was 3 cm; 144 (62%) were ERBB2 (formerly HER2)-positive, and 43 (18%) were triple negative. Most (212 [91%]) received doxorubicin-based NAC; 205 (88%) received adjuvant radiotherapy (RT), and 164 (70%) also received nodal RT. At a median follow-up of 40 months, there was 1 axillary nodal recurrence synchronous with local recurrence in a patient who refused RT. Among patients who received RT (n = 205), there were no nodal recurrences. CONCLUSIONS AND RELEVANCE: This cohort study found that in patients with cN1 disease rendered cN0 with NAC, with 3 or more negative SLNs with SLNB alone, nodal recurrence rates were low, without routine nodal clipping. These findings potentially support omitting ALND in such patients.

Accuracy of Magnetic Resonance Imaging-Guided Biopsy to Verify Breast Cancer Pathologic Complete Response After Neoadjuvant Chemotherapy: A Nonrandomized Controlled Trial.

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.

Concordance Between 21-Gene Recurrence Scores in Multifocal or Multicentric Breast Carcinomas Differs by Age and Histologic Subtype.

BACKGROUND: Among patients with multifocal or multicentric (MF/MC) breast cancer (BC) of similar morphology, concordance in Oncotype DX recurrence scores (RS) between tumors has been reported to be 87%. The effect of age and variation in histologic subtypes on RS concordance according to TAILORx criteria is unknown. METHODS: We identified patients with MF/MC, estrogen receptor-positive, HER2-negative, node-negative BC with two or more RS results treated at our institution from 2009 to 2018. Patients were analyzed by age group (≤ 50 and > 50 years). Low- and high-risk cut-offs were RS ≤ 25 and > 25 for age > 50 years, and RS ≤ 20 and > 20 for age ≤ 50 years. RS concordance was defined as no change in management based on RS variation between lesions. RESULTS: Overall, 120 patients with MF/MC BC were identified-82 (68.3%) aged > 50 years and 38 (31.7%) aged ≤ 50 years. Patients aged ≤ 50 years had higher mean RS for both multifocal (20 vs. 14; p = 0.006) and multicentric (17 vs. 13; p = 0.003) tumors and more frequently had high-risk tumors (p < 0.0001). Among patients aged > 50 years, 95.1% had RS concordance between tumors (same subtype, 98.2%; variable subtype, 88.9%; p = 0.1). Among patients aged ≤ 50 years, RS concordance was 81.6%. CONCLUSIONS: Among patients with MF/MC BC, RS concordance was high, particularly in those aged > 50 years with tumors of the same histologic subtype. RS testing of one focus may be sufficiently prognostic and predictive in patients aged > 50 years, regardless of subtype concordance. Testing of individual foci should be considered in patients aged ≤ 50 years due to a higher likelihood of RS discordance.

A machine learning model that classifies breast cancer pathologic complete response on MRI post-neoadjuvant chemotherapy.

BACKGROUND: For breast cancer patients undergoing neoadjuvant chemotherapy (NAC), pathologic complete response (pCR; no invasive or in situ) cannot be assessed non-invasively so all patients undergo surgery. The aim of our study was to develop and validate a radiomics classifier that classifies breast cancer pCR post-NAC on MRI prior to surgery. METHODS: This retrospective study included women treated with NAC for breast cancer from 2014 to 2016 with (1) pre- and post-NAC breast MRI and (2) post-NAC surgical pathology report assessing response. Automated radiomics analysis of pre- and post-NAC breast MRI involved image segmentation, radiomics feature extraction, feature pre-filtering, and classifier building through recursive feature elimination random forest (RFE-RF) machine learning. The RFE-RF classifier was trained with nested five-fold cross-validation using (a) radiomics only (model 1) and (b) radiomics and molecular subtype (model 2). Class imbalance was addressed using the synthetic minority oversampling technique. RESULTS: Two hundred seventy-three women with 278 invasive breast cancers were included; the training set consisted of 222 cancers (61 pCR, 161 no-pCR; mean age 51.8 years, SD 11.8), and the independent test set consisted of 56 cancers (13 pCR, 43 no-pCR; mean age 51.3 years, SD 11.8). There was no significant difference in pCR or molecular subtype between the training and test sets. Model 1 achieved a cross-validation AUROC of 0.72 (95% CI 0.64, 0.79) and a similarly accurate (P = 0.1) AUROC of 0.83 (95% CI 0.71, 0.94) in both the training and test sets. Model 2 achieved a cross-validation AUROC of 0.80 (95% CI 0.72, 0.87) and a similar (P = 0.9) AUROC of 0.78 (95% CI 0.62, 0.94) in both the training and test sets. CONCLUSIONS: This study validated a radiomics classifier combining radiomics with molecular subtypes that accurately classifies pCR on MRI post-NAC.

Microscopic Extracapsular Extension in Sentinel Lymph Nodes Does Not Mandate Axillary Dissection in Z0011-Eligible Patients.

BACKGROUND: In the ACOSOG (American College of Surgeons Oncology Group) Z0011 trial and the AMAROS (After Mapping of the Axilla: Radiotherapy or Surgery?) trial, matted nodes with gross extracapsular extension (ECE), a risk factor for locoregional recurrence, were an indication for axillary lymph node dissection (ALND), but the effect of microscopic ECE (mECE) in the sentinel lymph nodes (SLNs) on recurrence was not examined. METHODS: Between 2010 and 2017, 811 patients with cT1-2N0 breast cancer and SLN metastasis were prospectively managed according to Z0011 criteria, with ALND for those with more than two positive SLNs or gross ECE. Management of mECE was not specified. In this study, we compare outcomes of patients with one to two positive SLNs with and without mECE, treated with SLN biopsy alone (n = 685). RESULTS: Median patient age was 58 years, and median tumor size was 1.7 cm. mECE was identified in 210 (31%) patients. Patients with mECE were older, had larger tumors, and were more likely to be hormone receptor positive and HER2 negative, have two positive SLNs, and receive nodal radiation. At a median follow-up of 41 months, no isolated axillary failures were observed. There were 11 nodal recurrences; two supraclavicular ± axillary, four synchronous with breast, and five with distant failure. The five-year rate of any nodal recurrence was 1.6% and did not differ by mECE (2.3% vs. 1.3%; p = 0.84). No differences were observed in local (p = 0.08) or distant (p = 0.31) recurrence rates by mECE status. CONCLUSIONS: In Z0011-eligible patients, nodal recurrence rates in patients with mECE are low after treatment with SLN biopsy alone, even in the absence of routine nodal radiation. The presence of mECE should not be considered a routine indication for ALND.

Is Clinical Exam of the Axilla Sufficient to Select Node-Positive Patients Who Downstage After NAC for SLNB? A Comparison of the Accuracy of Clinical Exam Versus MRI.

BACKGROUND: The National Comprehensive Cancer Network (NCCN) endorses sentinel lymph node biopsy (SLNB) in patients with clinically positive axillary nodes who downstage after neoadjuvant chemotherapy (NAC). In this study, we compared the accuracy of post-NAC MRI to clinical exam alone in predicting pathologic status of sentinel lymph nodes in cN1 patients. METHODS: We identified patients with T0-3, N1 breast cancer who underwent NAC and subsequent SLNB from March 2014 to July 2017. Patients were grouped based on whether a post-NAC MRI was done. MRI accuracy in predicting SLN status was assessed versus clinical exam alone. RESULTS: A total of 450 patients met initial study criteria; 269 were analyzed after excluding patients without biopsy-confirmed nodal disease, palpable disease after NAC, and failed SLN mapping. Median age was 49 years. Post-NAC MRI was done in 68% (182/269). Patients undergoing lumpectomy vs mastectomy more frequently received a post-NAC MRI (88 vs 54%, p < 0.001). All other clinicopathologic parameters were comparable between those who did and did not have a post-NAC MRI. Thirty percent (55/182) had abnormal lymph nodes on MRI. Among these, 58% (32/55) had a positive SLN on final pathology versus 42% (53/127) of patients with no abnormal lymph nodes on MRI and 52% (45/87) of patients who had clinical exam alone (p = 0.09). MRI sensitivity was 38%, specificity was 76%, and overall SLN status prediction accuracy was 58%. CONCLUSIONS: Post-NAC MRI is no more accurate than clinical exam alone in predicting SLN pathology in patients presenting with cN1 disease. Abnormal lymph nodes on MRI should not preclude SLNB.