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Triple-negative breast cancer (TNBC) is an aggressive subtype characterized by extensive intratumoral heterogeneity. To investigate the underlying biology, we conducted single-cell RNA-sequencing (scRNA-seq) of >1500 cells from six primary TNBC. Here, we show that intercellular heterogeneity of gene expression programs within each tumor is variable and largely correlates with clonality of inferred genomic copy number changes, suggesting that genotype drives the gene expression phenotype of individual subpopulations. Clustering of gene expression profiles identified distinct subgroups of malignant cells shared by multiple tumors, including a single subpopulation associated with multiple signatures of treatment resistance and metastasis, and characterized functionally by activation of glycosphingolipid metabolism and associated innate immunity pathways. A novel signature defining this subpopulation predicts long-term outcomes for TNBC patients in a large cohort. Collectively, this analysis reveals the functional heterogeneity and its association with genomic evolution in TNBC, and uncovers unanticipated biological principles dictating poor outcomes in this disease. Triple-negative breast cancer is highly heterogeneous and aggressive. Here, the authors utilise single-cell RNA sequencing to investigate this heterogeneity, and discover a subpopulation of cells associated with metastasis and treatment resistance signatures, and linked to long term survival outcomes.

Identifying risk factors for lymphedema in patients treated for breast cancer has become increasingly important, given the current lack of standardization surrounding diagnosis and treatment. Reports on the association of body mass index (BMI) and weight change with lymphedema risk are conflicting. We sought to examine the impact of pre-operative BMI and post-treatment weight change on the incidence of lymphedema. From 2005 to 2011, 787 newly diagnosed breast cancer patients underwent prospective arm volume measurements with a Perometer pre- and post-operatively. BMI was calculated from same-day weight and height measurements. Lymphedema was defined as a relative volume change (RVC) of ≥10 %. Univariate and multivariate Cox proportional hazards models were used to evaluate the association between lymphedema risk and pre-operative BMI, weight change, and other demographic and treatment factors. By multivariate analysis, a pre-operative BMI ≥30 was significantly associated with an increased risk of lymphedema compared to a pre-operative BMI <25 and 25- <30 ( p  = 0.001 and p  = 0.012, respectively). Patients with a pre-operative BMI 25- <30 were not at an increased risk of lymphedema compared to patients with a pre-operative BMI <25 ( p  = 0.409). Furthermore, a cumulative absolute weight fluctuation of 10 pounds gained/lost per month post-operatively significantly increased risk of lymphedema (HR: 1.97, p  = < 0.0001). In conclusion, pre-operative BMI of ≥30 is an independent risk factor for lymphedema, whereas a BMI of 25- <30 is not. Large post-operative weight fluctuations also increase risk of lymphedema. Patients with a pre-operative BMI ≥30 and those who experience large weight fluctuations during and after treatment for breast cancer should be considered at higher-risk for lymphedema. Close monitoring or early intervention to ensure optimal treatment of the condition may be appropriate for these patients.

PurposeObtaining tumor-free surgical margins is critical to prevent recurrence in breast-conserving surgery but it remains challenging. We assessed the LUM Imaging System for real-time, intraoperative detection of residual tumor.MethodsLumpectomy cavity walls and excised specimens of breast cancer lumpectomy patients were assessed with the LUM Imaging System (Lumicell, Inc., Wellesley MA) with and without intravenous LUM015, a cathepsin-activatable fluorescent agent. Fluorescence at potential sites of residual tumor was evaluated with a sterile hand-held probe, displayed on a monitor and correlated with histopathology.ResultsBackground autofluorescence was assessed in excised specimens from 9 patients who did not receive LUM015. In vivo lumpectomy cavities and excised specimens were then imaged in 15 women undergoing breast cancer surgery who received no LUM015, 0.5, or 1 mg/kg LUM015 (5 women per dose). Among these, 11 patients had invasive carcinoma with ductal carcinoma in situ (DCIS) and 4 had only DCIS. Image acquisition took 1 s for each 2.6-cm-diameter surface. No significant background normal breast fluorescence was identified. Elevated fluorescent signal was seen from invasive cancers and DCIS. Mean tumor-to-normal signal ratios were 4.70 ± 1.23 at 0.5 mg/kg and 4.22 ± 0.9 at 1.0 mg/kg (p = 0.54). Tumor was distinguished from normal tissue in pre-and postmenopausal women and readings were not affected by breast density. Some benign tissues produced fluorescent signal with LUM015.ConclusionThe LUM Imaging System allows rapid identification of residual tumor in the lumpectomy cavity of breast cancer patients and may reduce rates of positive margins.

PurposeSafe breast cancer lumpectomies require microscopically clear margins. Real-time margin assessment options are limited, and 20–40% of lumpectomies have positive margins requiring re-excision. The LUM Imaging System previously showed excellent sensitivity and specificity for tumor detection during lumpectomy surgery. We explored its impact on surgical workflow and performance across patient and tumor types.MethodsWe performed IRB-approved, prospective, non-randomized studies in breast cancer lumpectomy procedures. The LUM Imaging System uses LUM015, a protease-activated fluorescent imaging agent that identifies residual tumor in the surgical cavity walls. Fluorescent cavity images were collected in real-time and analyzed using system software.ResultsCavity and specimen images were obtained in 55 patients injected with LUM015 at 0.5 or 1.0 mg/kg and in 5 patients who did not receive LUM015. All tumor types were distinguished from normal tissue, with mean tumor:normal (T:N) signal ratios of 3.81–5.69. T:N ratios were 4.45 in non-dense and 4.00 in dense breasts (p = 0.59) and 3.52 in premenopausal and 4.59 in postmenopausal women (p = 0.19). Histopathology and tumor receptor testing were not affected by LUM015. Falsely positive readings were more likely when tumor was present < 2 mm from the adjacent specimen margin. LUM015 signal was stable in vivo at least 6.5 h post injection, and ex vivo at least 4 h post excision.ConclusionsIntraoperative use of the LUM Imaging System detected all breast cancer subtypes with robust performance independent of menopausal status and breast density. There was no significant impact on histopathology or receptor evaluation.

BackgroundThe prevalence of same-day mastectomy with reconstruction has continued to increase across the United States in recent years. Prior studies have shown that same-day mastectomy with reconstruction leads to increased patient satisfaction and allows hospitals to use resources better. This study sought to evaluate the implementation of same-day mastectomy with a reconstruction recovery protocol for patients undergoing mastectomy at our institution.MethodsUnder an institutional review board-approved protocol, a retrospective cohort analysis compared patients who underwent mastectomy April 2016 through April 2017 with those who had mastectomy March 2020 through March 2021. Length of stay, postoperative intravenous (IV) opioid administration, safety end points, and cost were the main variables examined.ResultsThe study compared 457 patients in 2016–2017 with 428 patients in 2020–2021. The median hospital length of stay decreased from 24.6 h in 2016–2017 to 5.5 h in 2020–2021 (p < 0.001). The percentage of patients requiring postoperative IV opioids decreased from 69.1 % in 2016–2017 to 50 % in 2020–2021 (p < 0.001). The rates of unplanned readmissions within 30 days after mastectomy did not differ between the two groups, with a rate of 3.7 % in 2016–2017 and a rate of 5.1 % in 2020–2021 (p = 0.30). Reducing the rate of overnight admissions after mastectomy by 65.8 % resulted in a cost reduction of 65.8 %.ConclusionsImplementation of same-day mastectomy with a reconstruction protocol across a large academic center and two satellite sites was a safe alternative to conventional mastectomy recovery plans.

Purpose Extracting information from electronic medical record is a time-consuming and expensive process when done manually. Rule-based and machine learning techniques are two approaches to solving this problem. In this study, we trained a machine learning model on pathology reports to extract pertinent tumor characteristics, which enabled us to create a large database of attribute searchable pathology reports. This database can be used to identify cohorts of patients with characteristics of interest. Methods We collected a total of 91,505 breast pathology reports from three Partners hospitals: Massachusetts General Hospital, Brigham and Women’s Hospital, and Newton-Wellesley Hospital, covering the period from 1978 to 2016. We trained our system with annotations from two datasets, consisting of 6295 and 10,841 manually annotated reports. The system extracts 20 separate categories of information, including atypia types and various tumor characteristics such as receptors. We also report a learning curve analysis to show how much annotation our model needs to perform reasonably. Results The model accuracy was tested on 500 reports that did not overlap with the training set. The model achieved accuracy of 90% for correctly parsing all carcinoma and atypia categories for a given patient. The average accuracy for individual categories was 97%. Using this classifier, we created a database of 91,505 parsed pathology reports. Conclusions Our learning curve analysis shows that the model can achieve reasonable results even when trained on a few annotations. We developed a user-friendly interface to the database that allows physicians to easily identify patients with target characteristics and export the matching cohort. This model has the potential to reduce the effort required for analyzing large amounts of data from medical records, and to minimize the cost and time required to glean scientific insight from these data.

We evaluated whether time to surgery by race can be a health equity metric of surgical access. An observational analysis was performed using the National Cancer Database from 2010 to 2019. Inclusion criteria were women with stage I-III breast cancer. We excluded women with multiple cancers and whose diagnosis was made at a different hospital. The primary outcome variable was surgery within 90 days of diagnosis. A total of 886,840 patients were analyzed, with 76.8% White and 11.7% Black patients. 11.9% of patients experienced delayed surgery, which was significantly more common in Black patients than White patients. On adjusted analysis, Black patients were still significantly less likely to receive surgery within 90 days when compared to White patients (OR 0.61, 95% CI 0.58–0.63). The delay in surgery experienced by Black patients highlights the contribution of system factors in cancer inequity and should be a focus for targeted interventions. •Black patients are significantly more likely to experience delayed surgery.•The time to surgery increased for both lumpectomy and mastectomy over time.•The gap in time to surgery between White and Black women increased over time.

Background Eligibility for nipple-sparing mastectomy (NSM) varies widely on the basis of patient and tumor factors. Methods Review of patients undergoing NSM from June 2007 to December 2012 at our institution was performed. Patient and tumor characteristics, complications, and recurrences were collected. NSM from 2007 to 2010 and 2011 to 2012 were compared to assess trends in eligibility and outcomes over time. Results NSM was performed on 645 breasts in 370 patients. Indications were risk reduction in 330 (51.2 %), invasive cancer in 226 (35.0 %), and ductal carcinoma-in situ in 89 (13.8 %) breasts. Fifty-one (13.8 %) patients had positive lymph nodes. Twenty-seven (7.3 %) patients received neoadjuvant chemotherapy. Forty-eight (7.4 %) breasts had prior radiotherapy. Total nipple necrosis occurred in 11 (1.7 %) breasts. Twenty-four (3.7 %) breasts had nipples removed as a result of positive subareolar/nipple margins. At 22 months’ mean follow-up, local recurrence occurred in 4 of 156 (2.6 %) breasts operated on for cancer through 2011. No recurrences involved the nipple. NSM performed in 2011–2012 ( n  = 475) compared to 2007–2010 ( n  = 170), were more often for cancer, in patients with higher body mass index, and on larger breasts ( p  < 0.001). There was no significant difference in total nipple necrosis rates between groups. Nipple loss due to positive subareolar/nipple margins was significantly less in 2011–2012 ( p  = 0.027). Conclusions Eligibility for NSM has expanded to include women with higher body mass index and larger breasts, with no increase in nipple loss due to ischemia. Rates of positive subareolar margins have decreased over time, even though NSM is being performed more frequently for cancer, suggesting improved patient selection.

Background Nipple-sparing mastectomy (NSM) is an oncologically safe approach for breast cancer treatment and prevention; however, there are little long-term data to guide management for patients whose nipple margins contain tumor or atypia. Methods NSM patients with tumor or atypia in their nipple margin were identified from a prospectively maintained, single-institution database of consecutive NSMs. Patient and tumor characteristics, treatment, recurrence, and survival data were assessed. Results A total of 3158 NSMs were performed from June 2007 to August 2019. Nipple margins contained tumor in 117 (3.7%) NSMs and atypia only in 164 (5.2%) NSMs. Among 117 nipple margins that contained tumor, 34 (29%) margins contained invasive cancer, 80 (68%) contained ductal carcinoma in situ only, and 3 (3%) contained lymphatic vessel invasion only. Management included nipple-only excision in 67 (57%) breasts, nipple-areola complex excision in 35 (30%) breasts, and no excision in 15 (13%) breasts. Only 23 (24%) excised nipples contained residual tumor. At 67 months median follow-up, there were 2 (1.8%) recurrences in areolar or peri-areolar skin, both in patients with nipple-only excision. Among 164 nipple margins containing only atypia, 154 (94%) nipples were retained. At 60 months median follow-up, no patient with atypia alone had a nipple or areola recurrence. Conclusions Nipple excision is effective management for nipple margins containing tumor. No intervention is required for nipple margins containing only atypia. Our results support broad eligibility for NSM with careful nipple margin assessment.