Mastectomy or Margin Re-excision? A Nomogram for Close/Positive Margins After Lumpectomy for DCIS.

BACKGROUND: Anatomic extent of ductal carcinoma in situ (DCIS) may be uncertain in spite of clinical, pathologic, and imaging data. Consequently close/positive margins are common with lumpectomy for DCIS and often lead to a challenge in deciding whether to perform a re-excision or mastectomy. PATIENTS AND METHODS: From a single health system, we identified cases of lumpectomy for DCIS with close/positive margins who underwent re-excision for the purpose of constructing a nomogram. In total, 289 patients were available for analysis. The patients were randomly divided into two sets allocating 70% to the modeling and 30% to the validation set. A multivariable logistic regression model was used to estimate the probability of overall positive margin status using multiple clinicopathologic predictors. Nomogram validation included internal tenfold cross-validation, internal bootstrap validation, and external validation for which a concordance index was calculated to assess the external validity. RESULTS: Significant predictors of persistent positive margins from regression modeling included necrosis at diagnosis (non-comedo or comedo); DCIS not associated with calcifications on core biopsy; high-grade DCIS; progesterone receptor positivity; and number of positive margins at initial surgery. When subjected to internal validation, the nomogram achieved an uncorrected concordance index of 0.7332, a tenfold cross-validation concordance index of 0.6795, and a bootstrap-corrected concordance index of 0.6881. External validation yielded an estimated concordance index of 0.7095. CONCLUSION: Using clinical and pathologic variables from initial diagnosis and surgery for DCIS, this nomogram predicts persistent positive margins with margin re-excision, and may be a valuable tool in surgical decision-making.

Impact of Screening Mammography on Treatment in Young Women Diagnosed with Breast Cancer.

BACKGROUND: There is little data exploring the impact of screening mammography on subsequent treatment in the 40-49-year age group with breast cancer. We sought to assess the association between frequency of mammography in young women and extent of surgery and chemotherapy required. METHODS: An IRB-approved retrospective review was performed of patients diagnosed with breast cancer between ages 40 and 49 years from 1 January 2010 to 19 November 2018 within a single health system. Patients were grouped based on last screening 1-24 months prior to diagnosis (1-24 group), > 25 months prior to diagnosis (> 25 group), never screened, and > 25+ never screened (combination group). Multivariate logistic regression models were used to assess for associations between screening intervals and tumor and nodal stage, chemotherapy use, and extent of surgery. RESULTS: Of 869 patients included for analysis, 20% were never screened, 60% screened 1-24 months, and 19% screened > 25 months prior to diagnosis. Compared with the 1-24 months group, the never-screened group, > 25 months group, and combined group were more likely to receive chemotherapy. The never-screened and combined groups were more likely to undergo mastectomy and/or axillary lymph node dissection. Of patients undergoing upfront surgery, the > 25 months and combined groups were more likely to receive adjuvant chemotherapy, while the never-screened and combined groups were more likely to have nodal disease. CONCLUSION: Our findings support the initiation of screening mammography at age 40 years to reduce the risk of aggressive treatments for newly diagnosed breast cancers in this group.

Trends in neoadjuvant chemotherapy versus surgery-first in stage I HER2-positive breast cancer patients in the National Cancer DataBase (NCDB).

BACKGROUND: Neoadjuvant chemotherapy (NAC) is the standard of care for locally advanced HER2 + breast cancer (BC). Optimal sequencing of treatment (NAC vs. surgery first) is less clear cut in stage I (T1N0) HER2 + BC, where information from surgical pathology could impact adjuvant treatment decisions. Utilizing the NCDB, we evaluated the trend of NAC use compared to upfront surgery in patients with small HER2 + BC. METHODS: We identified NCDB female patients diagnosed with T1 N0 HER2 + BC from 2010 through 2015. Prevalence ratios (PR) using multivariable robust Poisson regression models were calculated to measure the association between baseline characteristics and the receipt of NAC. Analysis of trends over time was denoted by annual percent change (APC) of NAC versus surgery upfront. RESULTS: Of the 14,949 that received chemotherapy and anti-HER2 therapy during the study period, overall 1281 (8.6%) received NAC and 13,668 (91.4%) received adjuvant treatment. Patients receiving NAC increased annually from 4.2% in 2010 to 17.3% in 2015, with the most rapid increase occurring between years 2013 (8.5%) and 2014 (14.2%). The greatest increase was seen in patients with cT1c tumors with an APC of 37.8% over the study period (95% CI 29.0, 47.3%, p < 0.01), although a significant trend was likewise seen in patients with cT1a (APC = 26.1%,95% CI 1.59, 56.6%), and cT1b (APC = 27.4%, 95% CI 18.0, 37.7%) tumors. Predictors of neoadjuvant therapy receipt were age younger than 50 (PR = 1.69, 95% CI 1.52, 1.89), Mountain/Pacific area (PR = 1.24, 95% CI 1.05, 1.46), and estrogen receptor negativity (ER- PR + : PR = 2.01, 95% CI 1.51, 2.68; ER- PR- : PR = 1.49, 95% CI 1.32, 1.69). CONCLUSIONS: Neoadjuvant therapy for T1 N0 HER2 + BC increased over the study period and was mostly due increased use in clinical T1c tumors. This may be consistent with secular change in Pertuzumab treatment following FDA approval in 2013.

Adherence to NCCN Guidelines for Genetic Testing in Breast Cancer Patients: Who Are We Missing?

BACKGROUND: Genetic predisposition accounts for 5-10% of all breast cancers (BC) diagnosed. NCCN guidelines help providers identify appropriate candidates for counseling and testing. Concerns about underutilization of genetic testing have spurred interest in broader peri-diagnostic testing. We evaluated surgeon adherence to NCCN guidelines and studied patterns of testing in newly diagnosed BC patients. METHODS: A total of 397 patients were identified with newly diagnosed BC treated at our institution between 2016 and 2017 with no prior genetic testing. Eligibility for genetic testing based on NCCN criteria, referral, and patient compliance were recorded. RESULTS: In total, 212 of 397 (53%) met NCCN testing criteria. Fifty-nine of 212 (28%) patients went untested despite meeting one or more criteria. Fourteen of 59 (24%) of these were referred but did not comply. Most common criteria for meeting eligibility for testing both in the overall cohort and among missed patients were family history-based. Age > 45 years old and non-Ashkenazi Jewish descent were predictive of missed referral (p < 0.01). We identified pathogenic mutations in 16 of 153 (10%) patients who did undergo testing (11 (7%) BRCA1 or 2 and 5 (3%) with other predisposition gene mutations) or 16 of 397 (4%) among the overall group. CONCLUSIONS: Our data highlight the underutilization of genetic testing. Even in the setting of a full-service breast center with readily available genetic counseling, there is a substantial miss rate for identifying eligible patients, related to assessment of family history, patient age, and ethnicity, as well as patient compliance. Broader peri-diagnostic testing should be considered, and higher compliance rates with patients referred should be sought.

Response in breast vs axilla after neoadjuvant treatment and implications for nonoperative management of invasive breast cancer.

Improved imaging and neoadjuvant chemotherapy (NAT) have led to higher pathologic complete response rates (pCR) in patients with invasive breast cancer. This has questioned the necessity of surgery and axillary lymph node (ALN) dissection in these patients. Prospective clinical trials are implementing extensive core biopsies of the tumor bed of patients with clinical complete response as a means to identify and spare them breast surgery. In addition, it is anticipated that patients with pCR are most likely going to have no or minimal disease in ALN as well. To verify the feasibility of these trials, we performed a pathologic analysis of all our patients who have undergone NAT from 2009 to present. Using pathology data base, we identified 362 patients treated with neoadjuvant chemotherapy followed by surgery. Clinical and pathologic information including gross and microscopic descriptions as well as biomarker status was collected. pCR was 50% for patients with negative ALN pretreatment but only 28% for patients with positive ALN at diagnosis. Despite achieving pCR in the breast, up to 10% of patients with positive ALN and 1% with negative ALN had persistent disease. Eight percent of patients that were presumed to have no ALN disease either clinically and or by imaging were found to have metastatic carcinoma in ALN. The metastases were predominantly (80%) <5 mm, and not palpable on physical examination and or due to biopsy sampling error. pCR in breast and ALN directly correlated with tumor size, ALN disease, and Her2 positive and triple negative receptor phenotype. In breast cancer patients who are node positive at time of diagnosis with pCR in the breast after neoadjuvant chemotherapy, residual lymph node disease was very uncommon. Further study is warranted to select patients who may avoid breast and axillary surgery post neoadjuvant chemotherapy.

Does Surgical Margin Width Remain a Challenge for Triple-Negative Breast Cancer? A Retrospective Analysis.

Background and Objectives: Local and distant relapse (LR, DR) in breast cancer vary according to its molecular subtypes, with triple-negative breast cancer (TNBC) being the most aggressive. The surgical resection margin width (SRMW) for breast-conserving surgery (BCS) has been intensely debated, especially for the aforementioned subtype. The aim of this study was to examine the impact of SRMW on LR following BCS in TNBC patients. Materials and Methods: We conducted a retrospective study including all patients with TNBC for whom BCS was performed between 2005 and 2014. Results: Final analysis included a total of 92 patients, with a median tumor size of 2.5 cm (range 0-5 cm) and no distant metastasis at the time of diagnosis. A total of 87 patients had received neoadjuvant and/or adjuvant chemotherapy, and all patients had received adjuvant whole-breast radiotherapy. After a median follow-up of 110.7 months (95% CI, 95.23-126.166), there were 5 local recurrences and 8 regional/distant recurrences with an overall LR rate of 5.4%. The risk of LR and DR was similar between groups of patients with several SRMW cut-off values. Conclusions: Our study supports a safe "no ink on tumor" approach for TNBC patients treated with BCS.

Use of neoadjuvant versus adjuvant chemotherapy for hormone receptor-positive breast cancer: a National Cancer Database (NCDB) study.

INTRODUCTION: Neoadjuvant chemotherapy (NAC) is a well-established therapeutic option for patients with locally advanced disease often allowing downstaging and facilitation of breast conserving therapy. With evolution of better targeted treatment regimens and awareness of improved outcomes for significant responders, use of NAC has expanded particularly for triple negative and HER2-positive (HER2+) breast cancer. In this study, we explore utility of neoadjuvant chemotherapy for hormone receptor-positive HER2-negative (HR+ HER2-) patients. METHODS: Patients with HR+ HER2- breast cancer treated with chemotherapy before or after surgery were identified from 2010 to 2015 in the NCDB. Multivariable regression models adjusted for covariates were used to determine associations within these groups. RESULTS: Among 134,574 patients (clinical stage 2A, 64%; 2B, 21%; 3, 15%), 105,324 (78%) had adjuvant chemotherapy (AC) and 29,250 (22%) received NAC. Use of NAC increased over time (2010-2015; 13.2-19.4% and PR = 1.34 for 2015; p < 0.0001). Patients were more likely to receive NAC with cT3, cT4, and cN+ disease. Patients less likely to receive NAC were age ≥ 50, lobular carcinoma, increased Charlson-Deyo score, and government insurance. Complete response (pCR) was noted in 8.3% of NAC patients. Axillary downstaging occurred in 21% of patients, and predictors included age < 50 years, black race, poorly differentiated grade, invasive ductal histology, and either ER or PR negativity. CONCLUSIONS: NAC use among HR+ HER2- breast cancer patients has expanded over time and offers downstaging of disease for some patients, with pCR seen in only a small subset, but downstaging of the axilla in 21%. Further analysis is warranted to determine the subgroup of patients with HR+ HER2- disease who benefit from this approach.

Correction to: Technology for Intraoperative Margin Assessment in Breast Cancer.

In the original version of the article, some of the entries in Table 1 shifted during typesetting. The publisher regrets the error. The original article has been corrected. Following is the corrected table.

Technology for Intraoperative Margin Assessment in Breast Cancer.

BACKGROUND: As breast-conserving surgery (BCS) has become standard for treatment of breast cancer, the need for new technology to improve intraoperative margin assessment (IMA) has become clear. Close or positive margins during BCS lead to additional surgeries, treatment delay, additional stress for patients, and healthcare cost. Academia and industry have developed a diverse field of new technologies to allow surgeons to assess margins in the operating room. These technologies aim to reduce current rates of positive margins on final pathology. METHODS: We selected recently developed IMA technologies, some of which have undergone large clinical trials and others that are still in early stage development. Technologies were categorized based on underlying methodology to differentiate malignant and normal tissue: spectroscopy, electrical properties, optical imaging and molecular imaging. Additionally, this review details clinical investigations, relevant statistical analysis as well as strengths and weaknesses of the various technologies. CONCLUSION: Numerous technical innovations are being implemented to diminish rates of positive margins at breast tumor resection. Close collaboration among cross-disciplinary teams to further develop many of these technologies as well as completion of larger scale clinical studies are required to define an optimal approach. Development with an eye toward prioritizing sensitivity/specificity as well as healthcare cost containment has the potential to make a significant impact on this ongoing clinical need in breast cancer surgery.

Evaluation of surgically excised breast tissue microstructure using wide-field optical coherence tomography.

BACKGROUND: Currently, positive margins at lumpectomy contribute to health care cost, patient anxiety, and treatment delay. Multiple technology solutions are being explored with the aim of lowering re-excision rates for breast-conserving surgery (BCS). We examined wide-field optical coherence tomography (WF-OCT), an innovative adjunct intraoperative imaging tool for tissue visualization of margins. METHODS: This IRB-approved pilot study included women with invasive or in situ carcinoma scheduled for primary BCS. Lumpectomy specimens and any final/revised margins were imaged by optical coherence tomography immediately prior to standard histological processing. The optical coherence tomography used provided two-dimensional, cross-sectional, real-time depth visualization of the margin widths around excised specimens. A volume of images was captured for 10 × 10 cm tissue surface at high resolution (sub-30 µm) to a depth of 2 mm. Integrated interpretation was performed incorporating final pathology linked with the optical image data for correlation. RESULTS: Wide-field optical coherence tomography was performed on 185 tissue samples (50 lumpectomy specimens and 135 additional margin shaves) in 50 subjects. Initial diagnosis was invasive ductal carcinoma (IDC) in 10, ductal carcinoma in situ (DCIS) in 14, IDC/DCIS in 22, invasive lobular carcinoma (ILC) in 2, ILC/DCIS in 1, and sarcoma in 1. Optical coherence tomography was concordant with final pathology in 178/185 tissue samples for overall accuracy of 86% and 96.2% (main specimen alone and main specimen + shave margins). Of seven samples that were discordant, 57% (4/7) were considered close (DCIS < 2 mm from margin) per final pathology. CONCLUSION: Wide-field optical coherence tomography demonstrated concordance with histology at tissue margins, supporting its potential for use as a real-time adjunct intraoperative imaging tool for margin assessment. Further studies are needed for comprehensive evaluation in the intraoperative setting.

Observation versus excision of lobular neoplasia on core needle biopsy of the breast.

PURPOSE: Controversy surrounds management of lobular neoplasia (LN), [atypical lobular hyperplasia (ALH) or lobular carcinoma in situ (LCIS)], diagnosed on core needle biopsy (CNB). Retrospective series of pure ALH and LCIS reported "upgrade" rate to DCIS or invasive cancer in 0-40%. Few reports document radiologic/pathologic correlation to exclude cases of discordance that are the likely source of most upgrades, and there is minimal data on outcomes with follow-up imaging and clinical surveillance. METHODS: Cases of LN alone on CNB (2001-2014) were reviewed. CNB yielding LN with other pathologic findings for which surgery was indicated were excluded. All patients had either surgical excision or clinical follow-up with breast imaging. All cases included were subject to radiologic-pathologic correlation after biopsy. RESULTS: 178 cases were identified out of 62213 (0.3%). 115 (65%) patients underwent surgery, and 54 (30%) patients had surveillance for > 12 months (mean = 55 months). Of the patients who underwent surgical excision, 13/115 (11%) were malignant. Eight of these 13 found malignancy at excision when CNB results were considered discordant (5 DCIS, and 3 invasive lobular carcinoma), with the remainder, 5/115 (4%), having a true pathologic upgrade: 3 DCIS, and 2 microinvasive lobular carcinoma. Among 54 patients not having excision, 12/54 (22%) underwent subsequent CNB with only 1 carcinoma found at the initial biopsy site. CONCLUSIONS: Surgical excision of LN yields a low upgrade rate when careful consideration is given to radiologic/pathologic correlation to exclude cases of discordance. Observation with interval breast imaging is a reasonable alternative for most cases.

Defining the Need for Imaging and Biopsy After Mastectomy.

BACKGROUND: The proportion of patients eligible for breast-conservation therapy (BCT) yet opting for mastectomy is increasing. This decision is often driven by the desire to eliminate future screening and/or biopsy of the remaining breast or breasts. This study investigated the incidence of post-mastectomy imaging and biopsy. METHODS: A retrospective review of all unilateral mastectomy (UM) and bilateral mastectomy (BM) cases managed at a single institution was undertaken. Post-mastectomy imaging and biopsy rates were determined. RESULTS: Between 2009 and 2015, 185 UM and 200 BM cases managed for breast cancer were identified. The mean follow-up period was 30 months (range 3-75 months). For the patients with UM, imaging studies and biopsies done on the contralateral side were excluded given the standard of care for continued surveillance of the contralateral breast. Of the 185 UM patients, 19 (10%) underwent ipsilateral imaging (all ultrasounds) for physical examination findings, 11 (6%) underwent biopsy, and 2 (1%) had malignant findings. Of the 200 BM patients, 31 (15.5%) required imaging (29 ultrasounds and 2 MRIs), with 76% of the ultrasounds performed on the side with previous cancer. Subsequently, 16 (8%) of the BM patients had biopsy, with 11 (69%) of the 16 biopsies performed on the ipsilateral side. Three (1.5%) of the biopsies done on ipsilateral side demonstrated malignancy, whereas all the contralateral biopsies were benign. CONCLUSIONS: For 10-15.5% of patients who undergo mastectomy, either UM or BM, subsequent imaging is required, whereas 6-8% undergo biopsy. The yield of malignancy is low, approximately 1%. Thus, after mastectomy, the need for imaging and biopsy is not eliminated. This information is critical for patient understanding and expectation related to surgical decision making.

Impact of Screening Mammography on Treatment in Women Diagnosed with Breast Cancer.

BACKGROUND: Screening mammography reduces breast cancer mortality; however, screening recommendations, ordering, and compliance remain suboptimal and controversies regarding the value of screening persist. We evaluated the influence of screening mammography on the extent of breast cancer treatment. METHODS: Patients ≥ 40 years of age diagnosed with breast cancer from September 2008 to May 2016 at a single institution were divided into two groups: those with screening 1-24 months prior to diagnosis, and those with screening at 25+ months, including patients with no prior mammography. The association between the two groups and various clinical factors were assessed using logistic regression models. Subgroup analysis was performed based on age groups. RESULTS: Analysis included 1125 patients, 819 (73%) with screening at 1-24 months, and 306 (27%) with screening at 25+ months, including 65 (6%) who never had mammography. Overall, patients in the 25+ months group were more likely to receive chemotherapy [odds ratio (OR) 1.51, p = 0.0040], undergo mastectomy (OR 1.32, p = 0.0465), and require axillary dissection (AD; OR 1.66, p = 0.0045) than those in 1-24 months group. On subgroup analysis, patients aged 40-49 years with no prior mammography were more likely to have larger tumors (p = 0.0323) and positive nodes (OR 4.52, p = 0.0058), undergo mastectomy (OR 3.44, p = 0.0068), undergo AD (OR 4.64, p = 0.0002), and require chemotherapy (OR 2.52, p = 0.0287) than the 1-24 months group. CONCLUSIONS: Screening mammography is associated with decreased stage at diagnosis and receipt of less-extensive treatment. This was evident in all groups, including the 40-49 years age group, where controversy exists on whether screening is even necessary.

Physician preference and patient satisfaction with radioactive seed versus wire localization.

BACKGROUND: Nonpalpable breast lesions require localization before excision. This is most commonly performed with a wire (WL) or a radioactive seed (SL), which is placed into the breast under radiographic guidance. Although there are advantages of each modality, there are no guidelines to address which patients should undergo WL versus SL. We investigated factors influencing the selection of SL versus WL at our institution and assessed patient satisfaction with each procedure. METHODS: Patients undergoing preoperative localization of nonpalpable breast lesions from May 2014 through August 2015 were included. Physicians were surveyed on surgical scheduling to evaluate factors influencing the decision to perform SL or WL. Patient satisfaction was evaluated with a survey at the first postoperative visit. Retrospective chart review was performed. RESULTS: 341 patients were included: 104 (30%) patients underwent SL and 237 (70%) underwent WL. There was no difference in patient age, benign versus malignant disease, or need for concomitant axillary surgery comparing the SL versus WL groups. Physician survey indicated that 18% of patients were candidates for WL only. Of the patients who were eligible for both, 88 (41%) ultimately underwent SL and 126 (59%) had WL. The most commonly cited reason for selection of one localization method or the other was physician preference, followed by patient preference or avoiding additional visit. There was no significant difference in self-reported preoperative anxiety level, convenience of the localization procedure, pain of the localization procedure, operative experience, postoperative pain level or medication requirement, or overall patient satisfaction comparing patients who underwent SL and WL. CONCLUSIONS: SL and WL offer patients similar comfort and satisfaction. Factors influencing selection of one modality over the other include both logistic and clinical considerations.

Close and Positive Lumpectomy Margins are Associated with Similar Rates of Residual Disease with Additional Surgery.

BACKGROUND: Current guidelines state that "no ink on tumor" constitutes adequate surgical margins for lumpectomy specimens. However, there remains uncertainty when tumor is close (<1 mm) to multiple inked margins. METHODS: All local excisions for invasive breast cancer during 3 years at one center were reviewed. Tumor characteristics, margin status, patient age, reoperations, and pathology of reexcised specimen were recorded. Chi-square analysis and regression models were used to identify factors associated with residual disease upon reoperation. RESULTS: In 533 lumpectomies for invasive cancer, 60 (11 %) had at least one positive margin, and 106 (20 %) had one or more close margin. Multiple margins were either close or positive in 67 cases. Reoperation was performed in 125 of 533 cases (23 %) for close or positive margins. Positive margins were significantly more likely to undergo reoperation compared with close margins (p < 0.001). On reoperation, 73 of 125 (58 %) demonstrated residual cancer, including 39 of 68 (57 %) with close margins, and 34 of 57 (60 %) with positive margins (p = 0.52). When multiple margins were close or positive, residual cancer was found on reexcision in 45 of 59 (76 %) cases as opposed to 34 of 79 (43 %) cases with only one involved margin (p < 0.001). When controlling for other factors, positive margins were no more associated with residual disease than close margins (p = 0.32), whereas multiple close or positive margins were associated with significantly higher risk of residual disease (odds ratio 6.1; p = 0.002; 95 % confidence interval 2.6-14.45). CONCLUSIONS: The only significant predictor of residual tumor was multiple close or positive margins. It may be appropriate to recommend reexcision for patients with multiple close margins.

Breast pathology review: does it make a difference?

BACKGROUND: Breast pathology is a challenging field, and previous work has shown discrepancies in diagnoses, even among experts. We set out to determine whether mandatory pathology review changes the diagnosis or surgical management of breast disease. METHODS: Cases were referred for pathology review after patients presented for surgical opinion to the Dubin Breast Center at Mount Sinai Medical Center over the course of 2 years. Surgical pathologists with expertise in breast disease reviewed slides submitted from the primary institution and rendered a second opinion diagnosis. Comparison of these reports was performed for evaluation of major changes in diagnosis and definitive surgical management. RESULTS: A total of 306 patients with 430 biopsy specimens were reviewed. Change in diagnosis was documented in 72 (17 %) of 430 cases and change in surgical management in 41 (10 %). A change in diagnosis was more likely to occur in patients originally diagnosed with benign rather than malignant disease (31 vs. 7 %, p < 0.001). Twelve (7 %) of 169 specimens initially diagnosed as benign were reclassified as malignant. A malignant diagnosis was changed to benign in 4 (2 %) of 261 cases. Change in diagnosis was less common in specimens originating from commercial laboratories than community hospitals or university hospitals (8, 19, 21 %, p = 0.023). Change in management was not dependent on initial institution. Type of biopsy specimen (surgical or core) did not influence diagnostic or management changes. CONCLUSIONS: We recommend considering breast pathology review based on the individual clinical scenario, regardless of initial pathologic diagnosis or originating institution.

Breast cancer in male-to-female transsexuals: use of breast imaging for detection.

OBJECTIVE: The purposes of this article are to describe two cases of breast cancer in male-to-female transsexuals and to review eight cases previously reported in the literature. CONCLUSION: Breast cancer occurs in male-to-female transsexuals who receive high doses of exogenous estrogen and develop breast tissue histologically identical to that of a biologically female breast. This exposure to estrogen results in increased risk of breast cancer. The first patient described is a male-to-female transsexual with screening-detected ductal carcinoma in situ and a family history of breast cancer. The other patient is a male-to-female transsexual with invasive ductal carcinoma that was occult on diagnostic digital mammographic and ultrasound findings but visualized on digital breast tomosynthesis and breast MR images. The analysis of the eight previously reported cases showed that breast cancer in male-to-female transsexuals occurs at a younger age and is more frequently estrogen receptor negative than breast cancer in others born biologically male. Screening for breast cancer in male-to-female transsexuals should be undertaken for those with additional risk factors (e.g., family history, BRCA2 mutation, Klinefelter syndrome) and should be available to those who desire screening, preferably in a clinical trial.

Induced sensitization of tumor stroma leads to eradication of established cancer by T cells.

Targeting cancer cells, as well as the nonmalignant stromal cells cross-presenting the tumor antigen (Ag), can lead to the complete destruction of well-established solid tumors by adoptively transferred Ag-specific cytotoxic T lymphocytes (CTLs). If, however, cancer cells express only low levels of the Ag, then stromal cells are not destroyed, and the tumor escapes as Ag loss variants. We show that treating well-established tumors expressing low levels of Ag with local irradiation or a chemotherapeutic drug causes sufficient release of Ag to sensitize stromal cells for destruction by CTLs. This was shown directly using high affinity T cell receptor tetramers for visualizing the transient appearance of tumor-specific peptide-MHC complexes on stromal cells. Maximum loading of tumor stroma with cancer Ag occurred 2 d after treatment and coincided with the optimal time for T cell transfer. Under these conditions, tumor rejection was complete. These findings may set the stage for developing rational clinical protocols for combining irradiation or chemotherapy with CTL therapy.

The Breast Cancer Single-Cell Atlas: Defining cellular heterogeneity within model cell lines and primary tumors to inform disease subtype, stemness, and treatment options.

PURPOSE: Breast Cancer (BC) is the most diagnosed cancer in women; however, through significant research, relative survival rates have significantly improved. Despite progress, there remains a gap in our understanding of BC subtypes and personalized treatments. This manuscript characterized cellular heterogeneity in BC cell lines through scRNAseq to resolve variability in subtyping, disease modeling potential, and therapeutic targeting predictions. METHODS: We generated a Breast Cancer Single-Cell Cell Line Atlas (BSCLA) to help inform future BC research. We sequenced over 36,195 cells composed of 13 cell lines spanning the spectrum of clinical BC subtypes and leveraged publicly available data comprising 39,214 cells from 26 primary tumors. RESULTS: Unsupervised clustering identified 49 subpopulations within the cell line dataset. We resolve ambiguity in subtype annotation comparing expression of Estrogen Receptor, Progesterone Receptor, and Human Epidermal Growth Factor Receptor 2 genes. Gene correlations with disease subtype highlighted S100A7 and MUCL1 overexpression in HER2 + cells as possible cell motility and localization drivers. We also present genes driving populational drifts to generate novel gene vectors characterizing each subpopulation. A global Cancer Stem Cell (CSC) scoring vector was used to identify stemness potential for subpopulations and model multi-potency. Finally, we overlay the BSCLA dataset with FDA-approved targets to identify to predict the efficacy of subpopulation-specific therapies. CONCLUSION: The BSCLA defines the heterogeneity within BC cell lines, enhancing our overall understanding of BC cellular diversity to guide future BC research, including model cell line selection, unintended sample source effects, stemness factors between cell lines, and cell type-specific treatment response.

Innate immunity as a target for novel therapeutics in triple negative breast cancer.

INTRODUCTION: Currently, triple-negative breast cancer (TNBC) has limited therapeutic options beyond chemotherapy and has worse outcomes than other breast cancer subtypes. Initial experience with immune checkpoint blockade for the treatment of TNBC has indicated that modifying the tumor immune response represents a promising direction of investigation. Subsequent studies have led to a deeper understanding of the heterogeneity of this disease and have informed further exploration of numerous potential therapeutic approaches to intervene in the tumor microenvironment (TME). AREAS COVERED: Initial work in this arena has focused on enhanced definition of checkpoints in activation of an adaptive immune response. In this review, we discuss recent efforts that have looked into components of innate immunity to reverse immunosuppressive phenotypes and augment antitumor immune response. EXPERT OPINION: Current treatment options for TNBC have been improved with the approval of immune checkpoint inhibitors (ICI) in both advanced and early-stage disease; however, the challenge remains to expand the number of patients that will benefit from immunotherapy. Optimizing the innate immune response represents an opportunity to improve this therapeutic index, and the development of an array of novel agents is underway. Success will depend on precision characterization of the patient TME and selection of ideal combination therapy.