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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–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.

The 17th St Gallen International Breast Cancer Consensus Conference in 2021 was held virtually, owing to the global COVID-19 pandemic. More than 3300 participants took part in this important bi-annual critical review of the 'state of the art' in the multidisciplinary care of early-stage breast cancer. Seventy-four expert panelists (see Appendix 1) from all continents discussed and commented on the previously elaborated consensus questions, as well as many key questions on early breast cancer diagnosis and treatment asked by the audience. The theme of this year's conference was 'Customizing local and systemic therapies.' A well-organized program of pre-recorded symposia, live panel discussions and real-time panel voting results drew a worldwide audience of thousands, reflecting the farreaching impact of breast cancer on every continent. The interactive technology platform allowed, for the first time, audience members to ask direct questions to panelists, and to weigh in with their own vote on several key panel questions. A hallmark of this meeting was to focus on customized recommendations for treatment of early-stage breast cancer. There is increasing recognition that the care of a breast cancer patient depends on highly individualized clinical features, including the stage at presentation, the biological subset of breast cancer, the genetic factors that may underlie breast cancer risk, the genomic signatures that inform treatment recommendations, the extent of response before surgery in patients who receive neoadjuvant therapy, and patient preferences. This customized approach to treatment requires integration of clinical care between patients and radiology, pathology, genetics, and surgical, medical and radiation oncology providers. It also requires a dynamic response from clinicians as they encounter accumulating clinical information at the time of diagnosis and then serially with each step in the treatment plan and follow-up, reflecting patient experiences and treatment response.

Background Breast cancer and ovarian cancer patients increasingly undergo germline genetic testing. However, little is known about cancer-specific mortality among carriers of a pathogenic variant (PV) in BRCA1/2 or other genes in a population-based setting. Methods Georgia and California Surveillance Epidemiology and End Results (SEER) registry records were linked to clinical genetic testing results. Women were included who had stages I-IV breast cancer or ovarian cancer diagnosed in 2013-2017, received chemotherapy, and were linked to genetic testing results. Multivariable Cox proportional hazard models were used to examine the association of genetic results with cancer-specific mortality. Results 22 495 breast cancer and 4320 ovarian cancer patients were analyzed, with a median follow-up of 41 months. PVs were present in 12.7% of breast cancer patients with estrogen and/or progesterone receptor-positive, HER2-negative cancer, 9.8% with HER2-positive cancer, 16.8% with triple-negative breast cancer, and 17.2% with ovarian cancer. Among triple-negative breast cancer patients, cancer-specific mortality was lower with BRCA1 (hazard ratio [HR] = 0.49, 95% confidence interval [CI] = 0.35 to 0.69) and BRCA2 PVs (HR = 0.60, 95% CI = 0.41 to 0.89), and equivalent with PVs in other genes (HR = 0.65, 95% CI = 0.37 to 1.13), vs noncarriers. Among ovarian cancer patients, cancer-specific mortality was lower with PVs in BRCA2 (HR = 0.35, 95% CI = 0.25 to 0.49) and genes other than BRCA1/2 (HR = 0.47, 95% CI = 0.32 to 0.69). No PV was associated with higher cancer-specific mortality. Conclusions Among breast cancer and ovarian cancer patients treated with chemotherapy in the community, BRCA1/2 and other gene PV carriers had equivalent or lower short-term cancer-specific mortality than noncarriers. These results may reassure newly diagnosed patients, and longer follow-up is ongoing.

Obesity is a risk factor for the development of post-menopausal breast cancer. Breast white adipose tissue (WAT) inflammation, which is commonly found in women with excess body fat, is also associated with increased breast cancer risk. Both local and systemic effects are probably important for explaining the link between excess body fat, adipose inflammation and breast cancer. The first goal of this cross-sectional study of 196 women was to carry out transcriptome profiling to define the molecular changes that occur in the breast related to excess body fat and WAT inflammation. A second objective was to determine if commonly measured blood biomarkers of risk and prognosis reflect molecular changes in the breast. Breast WAT inflammation was assessed by immunohistochemistry. Bulk RNA-sequencing was carried out to assess gene expression in non-tumorous breast. Obesity and WAT inflammation were associated with a large number of differentially expressed genes and changes in multiple pathways linked to the development and progression of breast cancer. Altered pathways included inflammatory response, complement, KRAS signaling, tumor necrosis factor α signaling via NFkB, interleukin (IL)6-JAK-STAT3 signaling, epithelial mesenchymal transition, angiogenesis, interferon γ response and transforming growth factor (TGF)-β signaling. Increased expression of several drug targets such as aromatase, TGF-β1, IDO-1 and PD-1 were observed. Levels of various blood biomarkers including high sensitivity C-reactive protein, IL6, leptin, adiponectin, triglycerides, high-density lipoprotein cholesterol and insulin were altered and correlated with molecular changes in the breast. Collectively, this study helps to explain both the link between obesity and breast cancer and the utility of blood biomarkers for determining risk and prognosis.

HER2 +- amplified breast cancer patients derive benefit from treatment with anti-HER2-targeted therapy. Though adjuvant treatment is based on final pathology, decisions regarding neoadjuvant chemotherapy are made in the preoperative setting with imaging playing a key role in staging. We examined the accuracy of pre-operative imaging in determining pathological tumor size (pT) in patients undergoing upfront surgery. Early (cT1–T2N0) HER2 + breast cancer patients who underwent upfront surgery between 2015 and 2016 were identified from a prospective institutional database. We compared data for both clinical and final pathologic stage. Only those who underwent magnetic resonance imaging (MRI), mammography, and ultrasound in the preoperative setting were included in the analysis. Adjuvant treatment regimens were reviewed. We identified 87 cT1–2N0 patients with invasive HER2 + breast cancer who underwent upfront surgery. Median age was 52 years (IQR 43, 58) and median tumor size was 1.1 cm (IQR 0.5, 1.6). Fifteen patients (17%) were upstaged to stage II/III based on final pathology. Thirty-seven patients were T1cN0 on final pathology; 8 were cT1a–bN0 preop and 12 had pT overestimated by MRI by an average of 1.5 cm (> 0.5–1.5 cm). Compared to both mammography and MRI, the imaging modality most predictive of pT was ultrasound (p = 0.000072 ultrasound vs mammography and 0.000042 ultrasound vs MRI). For small HER2 + cN0 tumors undergoing upfront surgery, ultrasound was the imaging modality most predictive of pT. MRI overestimated tumor size in approximately 40% of patients. MRI may not accurately discriminate low-volume tumor burden in the breast and carries the potential of overtreatment in the upfront setting.

As neoadjuvant chemotherapy (NAC) for breast cancer has become more widely used, so has nipple-sparing mastectomy. A common criterion for eligibility is a 1 cm tumor-to-nipple distance (TND), but its suitability after NAC is unclear. In this study, we examined factors predictive of negative nipple pathologic status (NS−) in women undergoing total mastectomy after NAC. Women with invasive breast cancer treated with NAC and total mastectomy from August 2014 to April 2018 at our institution were retrospectively identified. Following review of pre- and post-NAC magnetic resonance imaging (MRI) and mammograms, the association of clinicopathologic and imaging variables with NS− was examined and the accuracy of 1 cm TND on imaging for predicting NS− was determined. Among 175 women undergoing 179 mastectomies, 74% of tumors were cT1-T2 and 67% were cN+ on pre-NAC staging; 10% (18/179) had invasive or in situ carcinoma in the nipple on final pathology. On multivariable analysis, after adjusting for age, grade, and tumor stage, three factors, namely number of positive nodes, pre-NAC nipple-areolar complex retraction, and decreasing TND, were significant predictors of nipple involvement (p

Radiotherapy (RT) after breast-conserving surgery (BCS) halves the risk of local recurrence, and it is considered the standard of care for the vast majority of patients with early invasive breast cancer. However, the majority of patients treated with BCS will not recur locally, even in the absence of RT. Over the past several decades, the improved and widespread use of systemic therapy has significantly decreased the rate of local recurrence. This has stimulated interest in identifying favorable patient subsets not requiring RT. Randomized controlled trials have shown in women aged ≥ 70 years with stage I estrogen receptor-positive (ER+) tumors, RT can be safely omitted. To better identify patients with favorable prognosis, ongoing trials have incorporated biological markers and genomic assays. Despite great research efforts to de-escalate locoregional treatment, real-world data indicate that omission of RT in low-risk patients is inconsistent. Better decision-making is warranted to reduce overtreatment and financial toxicity.

Obesity is associated with an increased risk of breast cancer in post-menopausal women and decreased risk in pre-menopausal women. Conversely, in BRCA1/2 mutation carriers, pre-menopausal obesity is associated with early-onset breast cancer. Here we show that obese, pre-menopausal BRCA1/2 mutation carriers have increased levels of aromatase and inflammation in the breast, as occurs in post-menopausal women. In a prospective cohort study of 141 women with germline BRCA1 (n = 74) or BRCA2 (n = 67) mutations, leptin, and aromatase expression were higher in the breast tissue of obese versus lean individuals (P P P BRCA1/2 mutation carriers.

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.

Breast conservation therapy (BCT) is well established for the management of primary operable breast cancer, with oncologic outcomes comparable to those of mastectomy. It remains unclear whether re-conservation therapy (RCT) is suitable for those patients who develop ipsilateral breast tumor recurrence (IBTR), for whom mastectomy is generally recommended. We identified women who underwent BCT for invasive or ductal carcinoma in situ and developed IBTR as a first event, comparing the pattern of subsequent events and survival for those treated by RCT versus mastectomy. Of 16,968 patents who had BCT, 322 (1.9%) developed an isolated IBTR as a first event between 1999 and 2019. 130 (40%) had RCT and 192 (60%) mastectomy. Compared to mastectomy, the RCT patients were older (66 vs 53

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 ≥2 RS results treated at our institution from 2009 to 2018. Patients were analyzed by age group (≤50 and >50). Low- and high-risk cutoffs were RS ≤25 and >25 for >50 years and RS ≤20 and >20 for ≤50 years. RS concordance was defined as no change in management based on RS variation between lesions. RESULTS. One hundred twenty 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 (p50 years, 95.1% had RS concordance between tumors (same subtype, 98.2%; variable subtype, 88.9%; p=0.1). Among patients aged ≤50, RS concordance was 81.6%. CONCLUSIONS. Among patients with MF/MC BC, RS concordance was high, particularly in those aged >50 with tumors of the same histologic subtype. RS testing of one focus may be sufficiently prognostic and predictive in patients aged >50, regardless of subtype concordance. Testing of individual foci should be considered in patients aged ≤50 due to higher likelihood of RS discordance.

Metaplastic breast carcinoma (MBC) is a rare, aggressive subtype of breast cancer associated with poorer overall survival than other triple-negative breast cancers. This study sought to compare survival outcomes among histologic subtypes of MBC with those of non-metaplastic triple-negative breast cancer. Clinicopathologic and treatment data for all patients with non-metastatic, pure MBC undergoing surgery from 1995 to 2017 and for a large cohort of patients with other types of triple-negative breast cancer during that period were collected from an institutional database. The MBC tumors were classified as having squamous, spindle, heterologous mesenchymal, or mixed histology. Survival outcomes were compared using the Kaplan-Meier method. Of 132 MBC patients, those with heterologous mesenchymal MBC (n = 45) had the best 5-year overall and breast cancer-specific survival (BCSS, 88%; 95% confidence interval [CI], 0.78–0.99), whereas those with squamous MBC had the worst survival (BCSS, 56%; 95% CI, 0.32–0.79). Overall survival, BCSS, and recurrence-free survival were worse for the patients with MBC than for the patients who had non-MBC triple-negative breast cancer, with a clinicopathologically adjusted recurrence hazard ratio of 2.4 (95% CI, 1.6–3.3; p

PURPOSE: Upgrade rates of conventional ADH are reported at 10–30%; however, rates for ADH bordering on DCIS (ADH-BD) are largely unknown. We examined the upgrade rate of ADH-BD and core needle biopsy (CNB) features associated with upgrade. Surgical management in patients with concurrent ipsilateral breast cancer (BC) was also examined. METHODS: From 2000–2018, women with CNB diagnosis of ADH-BD were prospectively identified. Women with pure ADH-BD and concurrent ipsilateral ADH-BD/BC were analyzed separately, and upgrade rates were calculated. CNB features associated with upgrade and type of surgery were examined in women with pure ADH-BD; CNB features and concurrent pathology associated with upgrade were examined in women with ipsilateral BC. RESULTS: 108/236 (46%) patients with pure ADH-BD on CNB had DCIS (40%) or invasive carcinoma (6%) on surgical excision. DCIS or invasive carcinoma was more frequently found on excision of a mass that yielded ADH-BD on biopsy than excision of calcifications (65% vs. 38%; p

The American College of Surgeons Oncology Group (ACOSOG) Z0011 trial demonstrated the safety of omitting axillary lymph node dissection (ALND) in T1–T2cN0 patients with fewer than three positive sentinel nodes (SLNs) undergoing breast-conservation therapy. While microscopic extracapsular extension (mECE) > 2 mm is associated with increased nodal burden, the significance of extranodal tumor deposits (ETDs) in the axillary fat is uncertain. Consecutive patients with T1–T2cN0 breast cancer undergoing sentinel node biopsy and ALND for SLN metastases from January 2010 to December 2018 were identified. ETDs were defined as intravascular tumor emboli or metastatic deposits in the axillary fat. Clinicopathologic characteristics and nodal burden were compared by ETD status. Among 1114 patients, 113 (10%) had ETDs: 81 (72%) were intravascular tumor emboli and 32 (28%) were soft tissue deposits. Patients with ETDs had larger tumors (median 2.2 vs. 2.1 cm; p = 0.033) and more often had mECE (83% vs. 44%; p

Nipple-sparing mastectomy (NSM) is being performed increasingly for risk reduction in high-risk groups. There are limited data regarding complications and oncological outcomes in women undergoing bilateral prophylactic NSM. This study reviewed institutional experience with prophylactic NSM, and examined the indications, rates of postoperative complications, incidence of occult malignant disease and subsequent breast cancer diagnosis.Women who had bilateral prophylactic NSM between 2000 and 2016 were identified from a prospectively maintained database. Rates of postoperative complications, incidental breast cancer, recurrence and overall survival were evaluated.A total of 192 women underwent 384 prophylactic NSMs. Indications included BRCA1 or BRCA2 mutations in 117 patients (60·9 per cent), family history of breast cancer in 35 (18·2 per cent), lobular carcinoma in situ in 29 (15·1 per cent) and other reasons in 11 (5·7 per cent). Immediate breast reconstruction was performed in 191 patients. Of 384 NSMs, 116 breasts (30·2 per cent) had some evidence of skin necrosis at follow-up, which resolved spontaneously in most; only 24 breasts (6·3 per cent) required debridement. Overall, there was at least one complication in 129 breasts (33·6 per cent); 3·6 and 1·6 per cent had incidental findings of ductal carcinoma in situ and invasive breast cancer respectively. The nipple-areola complex was preserved entirely in 378 mastectomies. After a median follow-up of 36·8 months, there had been no deaths and no new breast cancer diagnoses.These findings support the use of prophylactic NSM in high-risk patients. The nipples could be preserved in the majority of patients, postoperative complication rates were low, and, with limited follow-up, there were no new breast cancers.La mastectomía con preservación del pezón (nipple-sparing mastectomy, NSM) se realiza cada vez más para reducir riesgos en los grupos de pacientes de alto riesgo. Se dispone de pocos datos sobre complicaciones y resultados oncológicos en mujeres sometidas a NSM bilateral profiláctica. Este estudio revisó la experiencia institucional de la NSM profiláctica, y analizó las indicaciones, tasas de complicaciones postoperatorias, incidencia de enfermedad maligna oculta y diagnóstico de subsiguiente cáncer de mama. MÉTODOS: Se identificaron mujeres sometidas a NSM bilateral profiláctica durante el periodo 2000-2016 a partir de una base de datos prospectiva. Se evaluaron tasas de complicaciones postoperatorias, cáncer de mama incidental, recidiva y supervivencia global.Un total de 192 mujeres fueron sometidas a 384 NSMs profilácticas. Las indicaciones incluyeron mutaciones BRCA1 o BRCA2 en 117 (61%) pacientes, historia familiar de cáncer de mama en 35 (18%), carcinoma lobulillar in situ en 29 (15%) y otros motivos en 11 (5,7%). La reconstrucción mamaria inmediata se realizó en 191 pacientes. De las 384 NSMs, 116 (30%) presentaron alguna evidencia de necrosis de la piel durante el seguimiento y la mayoría se resolvieron de forma espontánea, con solo 24 (6,2%) mamas que requirieron desbridamiento. Globalmente hubo al menos una complicación en 129 (34%) mamas; 3,6% y 1,6% tuvieron hallazgos incidentales de carcinoma ductal in situ o cáncer de mama invasivo, respectivamente. El complejo areola-pezón se preservó completamente en 378 mastectomías. Tras una mediana de seguimiento de 36,8 meses, no hubo fallecimientos ni ningún diagnóstico nuevo de cáncer de mama. CONCLUSIÓN: Estos hallazgos apoyan la utilización de la NSM profiláctica en pacientes de alto riesgo. En la mayoría pacientes fue posible la preservación del pezón, las tasas de complicaciones postoperatorias fueron bajas y, con un seguimiento limitado, no hubo nuevos casos de cáncer de mama.

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 (median [IQR] age, 49 [40-58] years), 555 (91%) converted to cN0 and underwent SLNB; 234 (42%) had 3 or more negative SLNs and had SLNB alone. Median age was 49 years. Median tumor size was 3 cm; 144 (62%) wereERBB2(formerlyHER2)-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.

BACKGROUND In early studies, local recurrence (LR) rates were higher after neoadjuvant chemotherapy (NAC) in comparison with upfront surgery. Modern outcomes are uncertain, particularly among those who are initially breast-conserving surgery-ineligible (BCSi) and downstage to being breast-conserving surgery-eligible (BCSe). METHODS Among patients with cT1-3 breast cancer treated from 2014 to 2018 who were BCSe after NAC, clinicopathologic characteristics and LR were compared between initially BCSe patients and BCSi patients who downstaged. Breast-conserving surgery (BCS) eligibility was determined prospectively. RESULTS Among 685 patients, 243 (35%) were BCSe before and after NAC and had BCS; 282 (41%) were BCSi before NAC, downstaged to BCSe, and had BCS; and 160 (23%) were BCSi before NAC, downstaged to BCSe, and chose mastectomy. The median age was 52 years, and most cancers were cT1-2 (84%), cN+ (61%), and human epidermal growth factor receptor 2-positive (HER2+; 38%) or triple-negative (34%). Those who were BCSe before NAC had a lower cT stage, whereas those who chose mastectomy were younger (P < .05). NAC was usually ACT (doxorubicin, cyclophosphamide, and a taxane)-based (92%), 99% of HER2+ patients received dual blockade, and 99% of BCS patients received adjuvant radiation. At a median follow-up of 35 months, 22 patients (3.2%) had developed LR. The Kaplan-Meier 4-year LR rates were not different among the groups (1.9% for those who were BCSe before and after NAC, 6.3% for those who downstaged to being BCSe and underwent BCS, and 2.7% for those who downstaged and underwent mastectomy; P = .17). CONCLUSIONS LR rates are low after NAC and BCS, even among BCSi patients who downstage, and they are not improved in patients who downstage and choose mastectomy. Mastectomy can be safely avoided in BCSi patients who downstage with NAC.

INTRODUCTION: The contralateral prophylactic mastectomy (CPM) rate in the U.S. has been steadily increasing. This is of particular concern because many women who undergo this procedure are candidates for breast-conserving surgery. AREAS COVERED: CPM’s medical benefit is related to the risk of contralateral cancer development and whether CPM provides a survival benefit. Contralateral cancer rates have decreased, and CPM does not provide a survival benefit. Other potential benefits of the procedure may be improved quality of life; these data are reviewed. Research efforts have been undertaken to better understand the decision-making process of patients who consider, and ultimately undergo, this procedure. EXPERT OPINION: Decisional traits, personal values, the desire for peace of mind, and the desire to obtain breast symmetry are important factors that drive a woman’s decision to undergo CPM. Additionally, many patients lack knowledge on how different types of breast surgery impact outcomes. To improve the shared decision-making process, a stepwise approach to address possible misconceptions, and clarify the real risks/benefits of this procedure should be utilized. A clear recommendation (for/against) should be made for every patient with newly diagnosed breast cancer who considers CPM. Communication tools to assist patients and surgeons in this process are sorely needed.

Background: With advances in neoadjuvant chemotherapy (NAC), an increasing number of breast cancer patients achieve a pathologic complete response (pCR). Efforts are underway to non-invasively identify pCR in the breast, such that characterization of the concomitant nodal response will be invaluable for locoregional treatment planning. Here, we sought to evaluate the correlation between in-breast response and residual nodal disease among early stage breast cancer patients. Materials/Methods: We identified 728 patients who received NAC at our institution from 2006 to 2016. Breast and nodal response rates were evaluated and further stratified by clinicopathologic features, and biologic subtype approximation (hormone receptor positive [HR+], HER2 negative [HER2-] and low or intermediate grade = luminal A; HR+/HER2- and high grade = luminal B; HER2/neu-amplified = HER2+; ER-/HER2- = triple negative). Descriptive statistics and univariate analyses were employed to evaluate the correlation between breast and nodal response. Results: Of 728 patients, 269 (37%) were clinically node negative (cN0) and 459 (63%) were clinically node positive (cN+). Median age was 51 and median tumor size was 4.0cm (IQR 2.7 - 5.5cm). The cohort comprised 13% luminal A patients, 20% luminal B, 38% HER2, and 29% triple negative. Following NAC, the overall pCR rate (breast and nodes) was 29.8%. Among all cN0 patients who had a breast pCR (ypT0; n = 96), none exhibited residual nodal disease (100% ypN0). Among cN+ patients who had a breast pCR (n = 128), only 5.4% (n = 7) had residual nodal disease (ypN+). Rates of residual nodal disease among cN+ patients who achieved breast pCR varied by biologic subtype: luminal A patients with pCR in the breast had a 50.0% probability of residual nodal disease (n = 1/2 were ypT0N+), luminal B 6.7% (1/15), HER2+ 2.5% (2/80) and triple-negative 9.6% (3/31) (p=0.03). Conversely, among cN+ patients who exhibited nodal pCR following NAC, the rate of residual in-breast disease varied by receptor subtype: 80.0% of clinically node-positive luminal A patients who became ypN0 had residual in-breast disease (ypT+N0; n = 4/5), 60.0% of luminal B (21/35), 38.1% HER2+ (48/126), and 50.9% triple negative (29/57) (p=0.03). Conclusions: Among early stage breast cancer patients receiving NAC, in-breast pCR is predictive of nodal pCR. Among 96 cN0 patients who had in-breast pCR, we found none with residual nodal disease, representing a population that may be suitable for further limiting nodal therapy. The ability to pre-operatively identify in-breast pCR in this population would be particularly valuable if nodal pCR can consequently be inferred, potentially paving the way for studies of therapeutic de-escalation. Citation Format: Achraf Shamseddine, Jessica Flynn, Zhigang Zhang, Monica Morrow, Boris Mueller, Erin Gillespie, Atif Khan, Beryl McCormick, Oren Cahlon, Simon Powell, Andrea Barrio, Lior Z Braunstein. In-breast pathologic complete response (pCR) following neoadjuvant chemotherapy predicts nodal pCR in early stage breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-16-06.

Background Young age at breast cancer diagnosis is associated with negative prognostic outcomes, and breast cancer in black women often manifests at a young age. This study evaluated the effect of age on breast cancer management and outcomes in black women. Methods This was a retrospective cohort study of all black women treated for invasive breast cancer between 2005 and 2010 at a specialized tertiary-care cancer centre. Clinical and treatment characteristics were compared by age. Kaplan–Meier methodology was used to estimate overall survival (OS) and disease-free survival (DFS). Results A total of 666 black women were identified. Median BMI was 30 (range 17–56) kg/m2 and median tumour size was 16 (1–155) mm. Most tumours were oestrogen receptor-positive (66·4 per cent). Women were stratified by age: less than 40 years (74, 11·1 per cent) versus 40 years or more (592, 88·9 per cent). Younger women were significantly more likely to have a mastectomy, axillary lymph node dissection and to receive chemotherapy, and were more likely to have lymphovascular invasion and positive lymph nodes, than older women. The 5-year OS rate was 88·0 (95 per cent c.i. 86·0 to 91·0) per cent and the 5-year DFS rate was 82·0 (79·0 to 85·0) per cent. There was no statistically significant difference in OS by age (P = 0·236). Although DFS was inferior in younger women on univariable analysis (71 versus 88 per cent; P < 0·001), no association was found with age on multivariable analysis. Conclusion Young black women with breast cancer had more adverse pathological factors, received more aggressive treatment, and had worse DFS on univariable analysis. Young age at diagnosis was, however, not an independent predictor of outcome.

Nipple-sparing mastectomy (NSM) is increasingly performed for invasive breast cancer. Growing evidence supporting the oncologic safety of NSM has led to its widespread use and broadened indications. In this study, we examine the indications, complications, and long-term outcomes of therapeutic NSM. From 2003 to 2016, women undergoing NSM for invasive cancer or ductal carcinoma in situ (DCIS) were identified from a prospectively maintained database. Patient and disease characteristics were compared by procedure year, while complications were compared by procedure year using generalized mixed-effects models accounting for a random surgeon effect. Overall survival and time to recurrence were examined. Of the 467 therapeutic NSMs, 337 (72%) were invasive cancer, 126 (27%) were DCIS, and 4 (1%) were phyllodes tumors. Median age was 45 years (range 24–75) and median follow-up among survivors was 39.4 months. Three hundred and fifty-seven (76.4%) cases were performed in 2011 or after. When comparing NSMs performed before and after 2011, there was a significant increase in NSMs performed for invasive tumors (58% vs. 77%; p

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. 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). 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. 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.

Neoadjuvant chemotherapy (NAC) for breast cancer increases breast-conserving surgery (BCS) rates, but many women opt for mastectomy with contralateral prophylactic mastectomy (CPM). Here we evaluate factors associated with CPM use in women undergoing mastectomy post-NAC. A retrospective institutional NAC database review identified women with clinical stage I-III, unilateral invasive breast cancer undergoing unilateral mastectomy (UM) or CPM mastectomy from 9/2013 to 12/2017. Clinical/pathologic characteristics, imaging, and presence of contraindications to BCS post-NAC were compared, with subset analysis of BCS candidates. The multivariable analysis was adjusted for potential confounders. Five hundred sixty-nine women underwent mastectomy after NAC, 297 (52%) UM and 272 (48%) CPM. On univariable analysis, younger age, BRCA+, lower pre-NAC clinical stage, pathologic complete response, and axillary surgery extent were associated with CPM (all p

Context.— The American Society of Clinical Oncology/College of American Pathologists HER2 testing guideline in breast cancer was updated in 2018 to address issues on interpretation of uncommon results using dual-probe in situ hybridization according to the 2013 guideline. Objective.— To assess impact of the 2018 guideline on breast cancer with equivocal HER2 immunohistochemistry results. Design.— We retrospectively reviewed HER2 fluorescence in situ hybridization (FISH) data (HER2/CEP17 ratio and average HER2 copy number per cell) of HER2 immunohistochemistry–equivocal (2+ or 1+ to 2+) breast cancers at our center between January 2014 and May 2018 and compared HER2 FISH results according to 2013 and 2018 guidelines. Results.— A total of 1666 HER2 FISH results from 1421 patients with equivocal HER2 immunohistochemistry were reviewed. Based on the 2013 guideline, HER2 FISH results were amplified in 346 cases (20.8%), equivocal in 242 (14.5%), and nonamplified in 1078 (64.7%). Using the 2018 guideline, 258 cases (16%) were reclassified, including 242 previously equivocal test results (15%) and 16 previously positive results (1%) reclassified as negative. The subset of 2013 HER2-equivocal and 2018 HER2-nonamplified cases with HER2/CEP17 ratio lower than 2.0 and average HER2 copy number 4.0 or higher and lower than 6.0 showed higher incidence of micropapillary morphology compared with HER2-amplified cases. Despite most patients in this group not receiving HER2-targeted treatment, 96% had no evidence of disease at follow-up. Conclusions.— The 2018 guideline eliminated HER2 FISH–equivocal cases by reclassifying HER2-equivocal cases and cases with nonclassical amplification without HER2 overexpression as HER2 negative. As a consequence, we observed a considerable increase in HER2 FISH–negative cases and a slight decrease in HER2 FISH–positive cases.

False-negative (FN) intraoperative frozen section (FS) results of sentinel lymph nodes (SLN) have been reported to be more common after neoadjuvant chemotherapy (NAC) in the primary surgical setting. We evaluated SLN FS assessment in breast cancer patients treated with NAC to determine the FN rate and the histomorphologic factors associated with FN results. Patients who had FS SLN assessment following NAC from July 2008 to July 2017 were identified. Of the 711 SLN FS cases, 522 were negative, 181 positive, and 8 deferred. The FN rate was 5.4% (28/522). There were no false-positive results. Of the 8 deferred cases, 5 were positive on permanent section and 3 were negative. There was a higher frequency of micrometastasis and isolated tumor cells in FN cases (P

Purpose: Guidelines for early-stage breast cancer allow for radiotherapy (RT) omission following breast conserving surgery (BCS) among older women, though high utilization of RT persists. This study explores surgeon referral and the effect of a productivity-based bonus metric for radiation oncologists in an academic institution with centralized quality assurance (QA) review.Methods: We evaluated patients >70 years of age treated with BCS for ER+ pT1N0 breast cancer at a single tertiary cancer network between 2015-2018. 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=0.57). RT receipt was associated with younger patient age (70-74 years, OR 2.66, 95% 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 (KPS ³90, OR 5.34, 95% CI 2.63-10.83). Conclusion: Non-referral to radiation oncology accounted for half of RT omission, but was based on age and KPS, in accordance with guidelines. Lack of radiation oncologist practice change in response to misaligned financial incentives is reassuring, potentially reflecting centralized QA review. Multi-institutional studies are needed to confirm these findings.

Metaplastic breast carcinoma (MpBC) is a rare special histologic subtype of breast carcinoma characterized by the presence of squamous and/or mesenchymal differentiation. Most MpBCs are of triple-negative phenotype and neoadjuvant chemotherapy (NAC) is frequently utilized in patients with MpBC. The aim of this study was to evaluate response to NAC in a retrospective cohort of MpBCs. We identified 44 patients with MpBC treated with NAC at our center between 2002 and 2018. Median age was 48 years, 86% were clinical stage II–III, and 36% were clinically node-positive. Most (80%) MpBCs were triple-negative or low (1–10%) hormonal receptor positive and HER2 negative on pre-NAC biopsy. While on NAC, 49% showed no clinical response or clinico-radiological progression. Matrix-producing subtype was associated with clinico-radiological response (p = 0.0036). Post NAC, two patients initially ineligible for breast-conserving surgery (BCS) were downstaged to be eligible for BCS, whereas three patients potentially eligible for BCS before treatment became ineligible due to disease progression. Only one (2%) patient had a pathologic complete response (pCR). Among the 16 patients presenting with biopsy-proven clinical node-positive disease, 3 (19%) had nodal pCR. Axillary lymph node dissection was avoided in 3 (19%) patients who had successful axillary downstaging. Residual cancer burden (RCB) was assessed in 22 patients and was significantly associated with disease-free survival and overall survival. We observed a poor response or even disease progression on NAC among patients with MpBC, suggesting that NAC should be reserved for patients with inoperable MpBC.

Purpose Local recurrence after treatment of ductal carcinoma in situ (DCIS) with breast-conserving surgery (BCS) is more common than after mastectomy, but it is unclear if patterns of invasive recurrence vary by initial surgical therapy. Among patients with invasive recurrence after treatment for DCIS, we compared patterns of first recurrence between those originally treated with BCS vs. mastectomy. Methods From 2000 to 2016, women with an invasive recurrence occurring ≥ 6 months after initial treatment for DCIS were retrospectively identified. Clinicopathologic features and adjuvant treatment of the initial DCIS, as well as characteristics of first invasive recurrences, were compared between patients who had undergone BCS vs. mastectomy. Results 452 patients with an invasive recurrence after surgery for DCIS were identified: 367 patients (81%) had initially undergone BCS and 85 patients (19%) mastectomy. Patients originally treated with mastectomy were younger and were more likely to have had high grade, necrosis, and multifocal or multicentric DCIS (p p p = 0.12). Conclusions Among women who experienced a first invasive recurrence after treatment for DCIS, those who had originally undergone mastectomy more commonly presented with advanced disease compared to those treated with BCS, likely related to the absence of the breast and the higher risk profile of their initial DCIS.

Purpose/Objective(s) Following breast conserving surgery, the risk of ipsilateral in-breast recurrence is equivalent between whole breast radiation therapy (WBRT) and accelerated partial breast irradiation (APBI) in patients with low-risk tumors according to ASTRO guidelines. The Oncotype DX Recurrence Score (RS) is prognostic for both local and distant recurrence in ER+/HER2- breast cancer. Whether the RS can identify patients at increased risk for local recurrence among those considered eligible for APBI is unclear. Materials/Methods We retrospectively identified consecutive patients with clinical T1-2, ER+/HER2-, node-negative tumors with an available RS, and who were treated with APBI from 2010-2019 at a single institution. RS testing was performed for all patients with ER+/HER2-, invasive cancers ≥ 0.5 cm who were candidates for chemotherapy. Patients were considered for APBI based on the 2009 ASTRO guidelines. Characteristics were compared between patients with RS ≤ 25 and RS > 25 using Fisher's exact test for categorical variables and the Wilcoxon rank sum test for continuous variables. The 6-year cumulative incidence rate (CIR) of local recurrence was estimated using Kaplan-Meier methods and was compared between groups using the log-rank test. Results 223 patients were identified; the median (IQR) age was 63 years (57-68) and median (IQR) tumor size was 1.0 cm (0.8-1.4). 201 patients (90%) had RS ≤ 25 and 22 patients (10%) had RS > 25. Nine patients aged ≤ 50 years were included, all of whom had RS ≤ 25. Compared with the RS ≤ 25 group, patients with RS > 25 more frequently had tumors that were progesterone receptor negative (55% vs. 9%; P 25 group (97% vs. 95%; P = 0.39), as was median (IQR) duration of endocrine therapy at 3 years (2-5) for both groups (P = 0.9). The median (range) follow-up was 3.6 years (0.1-10.2) and was similar between groups (P = 0.64). Overall, 4 ipsilateral in-breast recurrences occurred during follow-up, with 2 events (1.0%) in the RS ≤ 25 group and 2 events (9.1%) in the RS > 25 group (P = 0.05). The 6-year CIR of local recurrence was higher among patients with RS > 25 compared with RS ≤ 25 (6-year CIR [95% CI] 0.01 [0-0.04] vs. 0.08 [0-0.21]; P = 0.006). Due to a low number of events, a multivariable analysis of factors associated with local recurrence could not be performed. Conclusion The overall risk of local recurrence following APBI in patients with early-stage, ER+ tumors is low, but our findings suggest that the RS may identify patients at increased risk for local failure among a favorable risk population. Prospective studies are needed to assess whether genomic profiling can be used for additional risk stratification for patients considered eligible for APBI, to identify patients for whom de-escalation of WBRT may not be advisable.

PURPOSE/OBJECTIVE(S) The use of neoadjuvant chemotherapy (NAC) in patients with operable breast cancer allows for assessment of treatment response, and subsequent tailoring of adjuvant therapy. While there is robust evidence demonstrating worse prognosis with residual disease versus path CR after NAC, there is little data regarding outcomes among patients with a heavy residual tumor burden after NAC. We report outcomes in patients who have exceptionally poor responses to NAC-those with > 9 nodes after NAC or with 5 cm or more of residual disease in the breast. MATERIALS/METHODS Between 06/2014 and 04/2020, 1511 patients 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. Those with 1-3 positive nodes after NAC were used as a comparison cohort. Recurrence and survival outcomes were compared based on residual disease burden after NAC. Clinicopathologic parameters were summarized with descriptive statistics. Overall survival and recurrence-free survival estimates were calculated using Kaplan Meier methodology. RESULTS Among 517 poor-responders, 315 patients had 1-3 positive nodes (N1a), 108 had 4-9 positive nodes (N2a), and 62 had > 9 positive nodes (high-volume residual, HVR); 32 patients with > 5cm of residual tumor in the breast were categorized as HVR. With a median follow-up of 39 months (IQR 27-50), the 5-year overall survival rate was 90% among N1a, 72% among N2a, and 78% among HVR patients (P = 0.003). The 5-year distant recurrence-free survival and local recurrence-free survival rates were 87%/87% among N1a vs. 59%/71% among N2a vs. 68%/75% among HVR (P < 0.001 and P = 0.009), respectively. 5-year local-regional and distant recurrence cumulative incidence rates, stratified by residual disease burden and by breast cancer subtype, are shown in Table 1. CONCLUSION Our work confirms that patients with high-volume residual are at high risk for LR and distant recurrence as well as death, despite best available standard-of-care treatment. ypN2a patients appear to perform as bad as HVR patients in terms of DM and death, but better in terms of local-regional recurrence. Triple-negative patients with residual disease had high rates of recurrence and death compared to other subtypes. Treatment intensification efforts are urgently needed.

Purpose Guidelines for early-stage breast cancer allow for radiotherapy (RT) omission following breast conserving surgery (BCS) among older women, though high utilization of RT persists. This study explores surgeon referral and the effect of a productivity-based bonus metric for radiation oncologists in an academic institution with centralized quality assurance (QA) review. Methods We evaluated patients ≥ 70 years of age treated with BCS for ER + pT1N0 breast cancer at a single institution between 2015–2018. 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 = 0.57). RT receipt was associated with younger patient age (70–74 years, OR 2.66, 95% 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 (KPS ≥90, OR 5.34, 95% CI 2.63–10.83). Conclusion Non-referral to radiation oncology accounted for half of RT omission, but was based on age and KPS, in accordance with guidelines. Lack of radiation oncologist practice change in response to misaligned financial incentives is reassuring, potentially reflecting centralized QA review. Multi-institutional studies are needed to confirm these findings.

PURPOSE Genetic testing is important for breast and ovarian cancer risk reduction and treatment, yet little is known about its evolving use. METHODS SEER records of women of age ≥ 20 years diagnosed with breast or ovarian cancer from 2013 to 2017 in California or Georgia were linked to the results of clinical germline testing through 2019. We measured testing trends, rates of variants of uncertain significance (VUS), and pathogenic variants (PVs). RESULTS One quarter (25.2%) of 187,535 patients with breast cancer and one third (34.3%) of 14,689 patients with ovarian cancer were tested; annually, testing increased by 2%, whereas the number of genes tested increased by 28%. The prevalence of test results by gene category for breast cancer cases in 2017 were BRCA1/2 , PVs 5.2%, and VUS 0.8%; breast cancer–associated genes or ovarian cancer–associated genes ( ATM, BARD1, BRIP1, CDH1, CHEK2, EPCAM, MLH1, MSH2, MSH6, NBN, NF1, PALB2, PMS2, PTEN, RAD51C, RAD51D, STK11, and TP53), PVs 3.7%, and VUS 12.0%; other actionable genes ( APC, BMPR1A, MEN1, MUTYH, NF2, RB1, RET, SDHAF2, SDHB, SDHC, SDHD, SMAD4, TSC1, TSC2, and VHL) PVs 0.6%, and VUS 0.5%; and other genes, PVs 0.3%, and VUS 2.6%. For ovarian cancer cases in 2017, the prevalence of test results were BRCA1/2, PVs 11.0%, and VUS 0.9%; breast or ovarian genes, PVs 4.0%, and VUS 12.6%; other actionable genes, PVs 0.7%, and VUS 0.4%; and other genes, PVs 0.3%, and VUS 0.6%. VUS rates doubled over time (2013 diagnoses: 11.2%; 2017 diagnoses: 26.8%), particularly for racial or ethnic minorities (47.8% Asian and 46.0% Black, v 24.6% non-Hispanic White patients; P < .001). CONCLUSION A testing gap persists for patients with ovarian cancer (34.3% tested v nearly all recommended), whereas adding more genes widened a racial or ethnic gap in VUS results. Most PVs were in 20 breast cancer–associated genes or ovarian cancer–associated genes; testing other genes yielded mostly VUS. Quality improvement should focus on testing indicated patients rather than adding more genes.

BACKGROUND: In patients with a positive sentinel lymph node (SLN) after neoadjuvant chemotherapy (NAC), the likelihood of residual nodal disease at axillary dissection (ALND) is high. Whether non-SLN metastasis frequency varies based on tumor subtype and SLN metastasis size is uncertain. We examined the association between tumor subtype and frequency of non-SLN metastases in patients with SLN micro vs macro metastases after NAC. METHODS: Patients with invasive breast cancer and a positive SLN biopsy after NAC between July 2008 and July 2019 were identified. Associations between tumor subtype, SLN disease volume, and frequency of non-SLN metastases were examined. RESULTS: Among 273 patients with ≥ 1 positive SLN and a completion ALND, mean age was 51 years, 87% of tumors were ductal, 80% were clinically node-positive at presentation, and 85% were cT2-3. The frequency of non-SLN metastases was non-significantly higher in HR+/HER2− (61%) vs. HER2+ (52%) and triple negative tumors (45%) (p = 0.09). Frequency of SLN micro metastasis was 9% for triple negative tumors compared with 17% for HR+/HER2− and 34% for HER2+ tumors (p = 0.015). Size of SLN metastasis (micro- vs. macrometastases) was not associated with non-SLN metastasis frequency or number within any subtype. CONCLUSIONS: In patients with a positive SLN after NAC, the likelihood of non-SLN metastasis at ALND was high across all tumor subtypes and did not vary significantly for SLN micro- versus macrometastases. ALND is recommended for SLN micro and macro metastases after NAC, irrespective of tumor subtype.

Axillary metastases in the form of palpable adenopathy indicate the need for neoadjuvant chemotherapy or axillary lymph node dissection (ALND). Patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2−) disease infrequently have nodal pathologic complete response to neoadjuvant chemotherapy and often require ALND. Sentinel lymph node biopsy is an accepted treatment for patients with two or fewer non-palpable nodal metastases who are undergoing breast conservation. The proportion of patients with HR+/HER2− disease with palpable adenopathy and two or fewer nodal metastases is unknown. Patients with cT1-T3N1 HR+/HER2− disease with palpable adenopathy were identified from a prospective database. Patients who underwent mastectomy or breast-conserving therapy with ALND were included in this study, whereas patients who received neoadjuvant chemotherapy were excluded. Clinicopathologic characteristics were compared between patients with two or fewer or more than two positive nodes on ALND. Of 180 patients included, 78 (43%) had two or fewer positive nodes on ALND, including 40/72 patients (56%) who underwent lumpectomy. On univariate analysis, cT1 tumor, unifocal tumor, only one palpable node, and two or fewer suspicious nodes on ultrasound were associated with two or fewer positive nodes on ALND. On multivariable analysis, number of suspicious nodes on ultrasound and cT stage were independently associated with two or fewer positive nodes on ALND. A substantial minority of patients with cT1-3N1 HR+/HER2− disease with palpable adenopathy had two or fewer positive nodes on ALND. Standard clinicopathologic features and ultrasound findings can help identify candidates for upfront sentinel lymph node biopsy as a strategy to avoid ALND. Prospective studies evaluating this approach are warranted.

Excess body fat and sedentary behavior are associated with increased breast cancer risk and mortality, including in normal weight women. To investigate underlying mechanisms, we examined whether adiposity and exercise impact the breast microenvironment (e.g., inflammation and aromatase expression) and circulating metabo-inflammatory factors. In a cross-sectional cohort study, breast white adipose tissue (WAT) and blood were collected from 100 women undergoing mastectomy for breast cancer risk reduction or treatment. Self-reported exercise behavior, body composition measured by dual-energy x-ray absorptiometry (DXA), and waist:hip ratio were obtained prior to surgery. Breast WAT inflammation (B-WATi) was assessed by IHC and aromatase expression was assessed by quantitative PCR. Metabolic and inflammatory blood biomarkers that are predictive of breast cancer risk and progression were measured. B-WATi was present in 56 of 100 patients and was associated with older age, elevated BMI, postmenopausal status, decreased exercise, hypertension and dyslipidemia (Ps < 0.001). Total body fat and trunk fat correlated with B-WATi and breast aromatase levels (Ps < 0.001). Circulating C-reactive protein, IL6, insulin, and leptin positively correlated with body fat and breast aromatase levels, while negative correlations were observed for adiponectin and sex hormone binding globulin (P < 0.001). Inverse relationships were observed with exercise (Ps < 0.05). In a subgroup of 39 women with normal BMI, body fat levels positively correlated with B-WATi and aromatase expression (Ps < 0.05). In conclusion, elevated body fat levels and decreased exercise are associated with protumorigenic micro- and host environments in normal, overweight, and obese individuals. These findings support the development of BMI-agnostic lifestyle interventions that target adiposity. Prevention Relevance: We report that individuals with high body fat and low exercise levels have breast inflammation, higher breast aromatase expression, and levels of circulating metabo-inflammatory factors that have been associated with increased breast cancer risk. These findings support interventions to lower adiposity, even among normal weight individuals, to prevent tumor growth.

Background Opioid-induced immunomodulation may be of particular importance in triple-negative breast cancer (TNBC) where an immune response is associated with improved outcome and response to immunotherapy. We evaluated the association between intraoperative opioids and oncological outcomes and explored patterns of opioid receptor expression in TNBC. Methods Consecutive patients with stage I–III primary TNBC were identified from a prospectively maintained database. Opioid receptor expression patterns in the tumour microenvironment were analysed using publicly available bulk and single-cell RNA-seq data. Results A total of 1143 TNBC cases were retrospectively analysed. In multivariable analysis, higher intraoperative opioid dose was associated with favourable recurrence-free survival, hazard ratio 0.93 (95% confidence interval 0.88–0.99) per 10 oral morphine milligram equivalents increase (P=0.028), but was not significantly associated with overall survival, hazard ratio 0.96 (95% confidence interval 0.89–1.02) per 10 morphine milligram equivalents increase (P=0.2). Bulk RNA-seq analysis of opioid receptors showed that OPRM1 was nearly non-expressed. Compared with normal breast tissue OGFR, OPRK1, and OPRD1 were upregulated, while TLR4 was downregulated. At a single-cell level, OPRM1 and OPRD1 were not detectable; OPRK1 was expressed mainly on tumour cells, whereas OGFR and TLR4 were more highly expressed on immune cells. Conclusions We found a protective effect of intraoperative opioids on recurrence-free survival in TNBC. Opioid receptor expression was consistent with a net protective effect of opioid agonism, with protumour receptors either not expressed or downregulated, and antitumour receptors upregulated. In this era of personalised medicine, efforts to differentiate the effects of opioids across breast cancer subtypes (and ultimately individual patients) should continue.

Neoadjuvant endocrine therapy (NET) is effective in downstaging large hormone receptor-positive (HR+) breast cancers and increasing rates of breast-conserving surgery (BCS), but data regarding nodal pathologic complete response (pCR) are sparse. We reported nodal and breast downstaging rates with NET, and compared axillary response rates following NET and neoadjuvant chemotherapy (NAC). Consecutive stage I–III breast cancer patients treated with NET and surgery from January 2009 to December 2019 were identified from a prospectively maintained database. Nodal pCR rates were compared between biopsy-proven node-positive patients treated with NET, and HR+/HER2- patients treated with NAC from November 2013 to July 2019. 127 cancers treated with NET and 338 with NAC were included. NET recipients were older, more likely to have lobular and lower-grade tumors, and higher HR expression. With NET, the nodal pCR rate was 11% (4/38) of biopsy-proven cases, and the breast pCR rate was 1.6% (2/126). Nodal-dowstaging rates with NET and NAC were not significantly different (11% vs 18%; P = 0.37). Patients achieving nodal pCR with NET versus NAC were older (median age 70 vs 50, P = 0.004) and had greater progesterone receptor (PR) expression (85% vs 13%, P = 0.031), respectively. Of patients not candidates for BCS due to a large tumor relative to breast size, 36/47 (77%) became BCS-eligible with NET (median PR expression 55% vs 5% in those remaining ineligible, P

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

The efficacy of chemoprevention for breast cancer risk reduction has been demonstrated in randomized controlled trials; however, use remains low. We sought to determine whether uptake differed by risk factors, and to identify reasons for refusal and termination. Women seen in a high-risk clinic from October 2014 to June 2017 considered eligible for chemoprevention (history of lobular carcinoma in situ, atypia, family history of breast/ovarian cancer, genetic mutation, or history of chest wall radiation) were retrospectively identified. Breast cancer risk factors were compared among those with and without chemoprevention use, and compliance was noted. Overall, 1506 women were identified, 24% with prior/current chemoprevention use. Women ≥ 50 years of age were more likely to use chemoprevention than women

Background Both patients with inflammatory breast cancer (IFLBC) and patients with noninflammatory T4 breast cancer (non-IFLBC) have a heavy disease burden in the breast; whether the unique biology of IFLBC conveys a higher locoregional recurrence (LRR) risk and worse outcomes in comparison with other T4 lesions is uncertain. Here the outcomes of patients with IFLBC and patients with non-IFLBC treated with modern multimodality therapy are compared. Methods Patients with nonmetastatic T4 breast cancer treated with neoadjuvant chemotherapy, mastectomy, and radiation therapy between 2006 and 2016 were identified. Recurrences and survival were compared between patients with IFLBC and patients with non-IFLBC overall and stratified by receptor subtype. Results For 199 T4 patients, the median age was 52 years, and the median clinical tumor size was 7 cm. One hundred seventeen (59%) had IFLBC. With a median follow-up of 41 months, 4 patients had isolated LRR; all cases occurred in patients with IFLBC. The 5-year isolated LRR rate for patients with IFLBC was 4.8%. Overall, 14 patients had both LRR and distant recurrence (DR); 47 had DR only. The 5-year distant recurrence-free survival (DRFS) rates were similar for patients with IFLBC and patients with non-IFLBC (63% vs 71%; log-rank P = .14). The 5-year DRFS rate was lowest among triple-negative (TN) patients (43%) and was significantly lower for patients with TN IFLBC versus patients with non-IFLBC (28% vs 62%; log-rank P = .02). The 5-year overall survival rates (71% vs 74%; log-rank P = .4) and cancer-specific survival rates (74% vs 79%; log-rank P = .23) did not differ between IFLBC and non-IFLBC. Conclusions Although IFLBC is often considered a unique biologic subtype, patients with IFLBC and patients with non-IFLBC had similar outcomes with modern multimodality therapy; isolated LRR was uncommon. The TN subtype in patients with IFLBC is associated with poor outcomes, and this indicates the need for new treatment approaches in this group.

BACKGROUND. Low incidence of breast cancer in men (BCM) (65 years). Kaplan-Meier methods were used to compare overall survival (OS) and breast cancer-specific survival (BCSS). Competing-risk methods analyzed time to second primary cancers (SPCs), with any-cause death treated as a competing risk. RESULTS. The study identified 152 BCM patients with a median age of 64 years (range, 19–96 years). The median body mass index (BMI) was 28 kg/m(2). Men age 65 years or younger (n = 78, 51 %) were more overweight/obese than men older than 65 years (n = 74, 49 %) (89 % vs 74 %, respectively; P = 0.008). Both groups had similar nodal metastases rates (P = 0.4), estrogen receptor positivity (P = 1), and human epidermal growth factor receptor 2 (HER2)neu overexpression (P = 0.6). Men 65 years of age or younger were more likely to receive chemotherapy (P = 0.002). The median follow-up period was 5.8 years (range, 0.1–14.4 years). The 5-year OS was 86 % (95 % confidence interval [CI], 80–93 %), whereas the 5-year BCSS was 95 % (95 % CI, 91–99 %). The BCM patients 65 years of age and younger had better OS (P = 0.003) but not BCSS (P = 0.8). The 5-year cumulative incidence of SPC was 8.4 % (95 % CI, 3.4–13.4 %). The prior SPC rate was higher for men older than 65 years (n = 20, 31 %) than for those age 65 years or younger (n = 7, 11 %) (P = 0.008). This did not account for differences in life years at risk. No difference was observed in SPC cumulative incidence stratified by age (P = 0.3). CONCLUSIONS. Men 65 years of age or younger received more chemotherapy and had improved OS, but not BCSS compared with men older than 65 years. For all BCM, SPC is a risk, and appropriate screening may be warranted.

INTRODUCTION: Nipple-sparing mastectomy (NSM) is increasingly used for breast cancer risk reduction and treatment. Prior small studies with variable control for baseline characteristics suggest superior satisfaction with NSM. The aim of this study was to compare patient satisfaction following NSM and total mastectomy (TM) utilizing the BREAST-Q patient-reported outcome measure in a well-characterized patient population. METHODS: Patients at a single institution undergoing NSM or TM with immediate tissue expander/implant reconstruction who completed a follow-up BREAST-Q from 2007–2017 were identified by retrospective review of a prospective database. Baseline characteristics were compared, and linear mixed models were used to analyze associations with BREAST-Q scores over time. RESULTS: Of 1866 eligible patients, 219 (12%) underwent NSM, and 1647 (88%) underwent TM. Median time from baseline to BREAST-Q was 658 days. Patients having NSM were younger, more likely to be white, and had lower BMI. They more often had prophylactic surgery, bilateral mastectomies, lower-stage disease, and less often received chemotherapy/radiation than patients having TM. On multivariable analysis, after controlling for relevant clinical variables, there was no difference in satisfaction with breasts or satisfaction with outcome overall between NSM and TM patients. Psychosocial well-being and sexual well-being were significantly higher in the NSM group. After additionally controlling for pre-operative BREAST-Q score in a subset of patients (72 NSM; 443 TM), only psychosocial well-being remained significantly higher in NSM patients. CONCLUSION: Patient-reported outcomes should be discussed with women weighing the risks and benefits of NSM to provide a better understanding of expected quality of life.

Breast cancer treatment is multidisciplinary. The majority of women with early-stage breast cancer are candidates for breast-conserving surgery with radiotherapy or mastectomy. The risk of local recurrence and the chance of survival does not differ with these approaches. Sentinel node biopsy is used for axillary staging, and individualized approaches are minimizing the need for axillary dissection in sentinel node-positive women. Adjuvant systemic therapy is used in the majority of women based on proven survival benefit, and molecular profiling to individualize treatment based on risk is now a clinical reality for patients with hormone receptor-positive cancers. Follow-up surveillance consists of a history, physical examination, and annual mammography. Following adjuvant systemic treatment, there is currently no evidence that routine imaging improves outcomes in the absence of symptoms. Novel modalities for early tumor detection are welcomed, but will need to demonstrate clinical utility in prospective trials.

Purpose Little is known about the extent to which genetic counseling is integrated into community practices for patients newly diagnosed with breast cancer. We examined the receipt of clinically indicated genetic counseling in these patients. Patients and Methods We surveyed 5,080 patients between the ages of 20 and 79 years, diagnosed from July 2013 to August 2015 with early-stage breast cancer and reported to the SEER registries of Georgia and Los Angeles County. Surveys were linked to SEER clinical data and genetic test results. The study sample (N = 1,711) comprised patients with indications for formal genetic risk evaluation. Results Overall, 47.4% did not get tested, 40.7% tested negative, 7.4% had a variant of uncertain significance only, and 4.5% had a pathogenic mutation. Three quarters (74.6%) received some form of genetic counseling (43.5%, formal counseling and 31.1%, physician-directed discussion). Virtually all tested patients (96.1%) reported some form of genetic discussion (62.2%, formal counseling and 33.9%, physician-directed discussion). However, only one half (50.6%) of those not tested received any discussion about genetics. Younger women were more likely to report some type of counseling, controlling for other factors: odds ratio, 4.5 (95% CI, 2.6 to 8.0); 1.9 (95% CI, 1.1 to 3.3); and 1.5 (95% CI, 1.0 to 2.3) for women younger than 50 years of age, 50 to 59 years of age, and 60 to 69 years of age versus those 70 years of age and older. Patients’ assessments of the amount of information they received about whether to get tested were similarly high whether they were counseled by a genetics expert or by a physician only (80.8% v 79.4% stated information was just right, P = .59). Conclusion Less than one half (43.5%) of patients with clinical indications received formal genetic counseling. There is a large gap between mandates for timely pretest formal genetic counseling in higher-risk patients and the reality of practice today.

BACKGROUND The omission of radiotherapy (RT) after lumpectomy is a reasonable option for many older women with favorable-prognosis breast cancer. In the current study, we sought to evaluate patient perspectives regarding decision making about RT. METHODS Women aged 65 to 79 years with AJCC 7th edition stage I and II breast cancer who were reported to the Georgia and Los Angeles County Surveillance, Epidemiology, and End Results registries were surveyed (response rate, 70%) regarding RT decisions, the rationale for omitting RT, decision-making values, and understanding of disease recurrence risk. We also surveyed their corresponding surgeons (response rate, 77%). Patient characteristics associated with the omission of RT were evaluated using multilevel, multivariable logistic regression, accounting for patient clustering within surgeons. RESULTS Of 999 patients, 135 omitted RT (14%). Older age, lower tumor grade, and having estrogen receptor-positive disease each were found to be strongly associated with omission of RT in multivariable analyses, whereas the number of comorbidities was not. Non-English speakers were more likely to omit RT (adjusted odds ratio, 5.9; 95% confidence interval, 1.4-24.5). The most commonly reported reasons for RT omission were that a physician advised the patient that it was not needed (54% of patients who omitted RT) and patient choice (41%). Risk of local disease recurrence was overestimated by all patients: by approximately 2-fold among those who omitted RT and by approximately 8-fold among those who received RT. The risk of distant disease recurrence was overestimated by approximately 3-fold on average. CONCLUSIONS To some extent, decisions regarding RT omission are appropriately influenced by patient age, tumor grade, and estrogen receptor status, but do not appear to be optimally tailored according to competing comorbidities. Many women who are candidates for RT omission overestimate their risk of disease recurrence. Cancer 2018;124:2714-2723. © 2018 American Cancer Society.