AMACR Expression is a Potential Diagnostic Marker in Apocrine Lesions of Breast, and is Associated with High Histologic Grade and Lymph Node Metastases in Some Invasive Apocrine Breast Cancers.

BACKGROUND: Carcinoma with apocrine differentiation (AC) is a subtype of breast carcinoma with apocrine features in >90% of the tumor. Molecular studies demonstrate AC has high expression of androgen receptor (AR) mRNA. Pure AC lack estrogen receptor (ER), progesterone receptor (PR), and express AR, with variable human epidermal growth factor 2 (HER2) status. Currently, in triple negative AC, no targetable therapies or specific diagnostic markers exist. MATERIALS AND METHODS: α-Methylacyl CoA racemase (AMACR) expression was investigated as a marker of apocrine differentiation using a single-plex immunoperoxidase stain, and a novel AMACR/p63 dual stain in a subset of cases, across 1) benign apocrine lesions (apocrine metaplasia, adenosis) 2) apocrine DCIS (ADCIS), 3) AC/ invasive ductal carcinoma (IDC) with apocrine features, 4) non-apocrine triple negative breast cancer (TNBC) and 5) IDC, no special type. A sub-set of cases were evaluated by tissue microarray. RESULTS: AMACR expression was increased in both AC and ADCIS, with minimal expression in benign breast tissue, TNBC and IDC, NST cases. In invasive cases, those with positive AMACR (>5% positivity) were significantly associated with higher histologic grade (P = .006), initial N stage (chi squared 0.044), and lack of ER or PR expression (both P < .001), with no correlation with overall survival. Analysis of TCGA breast cancer datasets revealed AMACR expression was significantly higher in molecularly defined apocrine carcinomas relative to basal and luminal subtypes. Moreover, high AMACR expression predicted worse relapse-free and distant-metastasis free survival, among both ER-/PR-/Her2- and ER-/PR-/Her2+ breast cancer cohorts (log-rank P = .081 and .00011, respectively). CONCLUSION: AMACR represents a promising diagnostic and prognostic marker in apocrine breast lesions. Further study is needed to determine the biologic and clinical significance of this protein in AC.

The Effect of Black Cohosh on Ki67 expression and Tumor Volume: A Pilot Study of Ductal Carcinoma in Situ Patients.

BACKGROUND: Black cohosh (BC) (Cimicifuga racemosa) may prevent and treat breast cancer through anti-proliferative, pro-apoptotic, anti-estrogenic, and anti-inflammatory effects. This study sought to evaluate the effect of BC on tumor cellular proliferation, measured by Ki67 expression, in a pre-operative window trial of ductal carcinoma in situ (DCIS) patients. METHODS: Patients were treated pre-operatively for 2 to 6 weeks with BC extract. Eligible subjects were those who had DCIS on core biopsy. Ki67 was measured using automated quantitative immunofluorescence (AQUA) pre/post-operatively. Ki67, tumor volume, and hormone changes were assessed with 2-sided Wilcoxon signed-rank tests, α = .05. RESULTS: Thirty-one patients were treated for an average of 24.5 days (median 25; range 15-36). Ki67 decreased non-significantly (n = 26; P = .20; median pre-treatment 1280, post-treatment 859; range pre-treatment 175-7438, post-treatment 162-3370). Tumor volume, estradiol, and FSH did not change significantly. No grade 3 or 4 adverse events were reported. CONCLUSIONS: BC use showed no significant impact on cellular proliferation, tumor volume, or invasive disease upgrade rates in DCIS patients. It was well-tolerated, with no observed significant toxicities. Further study is needed to elucidate BC's role in breast cancer treatment and prevention.ClinicalTrials.gov Identifier: NCT01628536https://clinicaltrials.gov/ct2/show/NCT01628536.

Breast Cancer Screening: Is There Room for De-escalation?

Purpose of Review: Breast cancer screening is highly controversial and different agencies have widely varying guidelines. Yet it is currently used extensively in the USA and frequently the thought is "the more, the better." The purpose of this review is to objectively assess the risks and benefits of screening mammography and consider whether there may be areas where it could be de-escalated. Recent Findings: Over the past few years, there have been several meta-analyses that are concordant, and it is now agreed that the main benefit of screening mammography is about a 20% reduction in breast cancer mortality. This actually benefits about 5% of patients with mammographically detected tumors. We now appreciate that the main harm of screening is overdiagnosis, i.e. detection of a cancer that will not cause the patient any harm and would not have ever been detected without the screening. This currently represents about 20 to 30% of screening detected cancers. Finding extra cancers with more intense screening is not always good, because in this situation, the risk of overdiagnosis increases and the benefit decreases. In some groups, the risk of overdiagnosis approaches 75%. Summary: Our goal should be not only to find more cancers, but to avoid finding cancers that would never have caused the patient any harm and lead to unnecessary treatment. The authors suggest some situations where it may be reasonable to de-escalate screening.

Association of Medicaid Expansion with Post-mastectomy Reconstruction Rates.

BACKGROUND: The Affordable Care Act sought to improve access to health care for low-income individuals. This study aimed to assess whether expansion of Medicaid coverage increased rates of post-mastectomy reconstruction (PMR) for patients who had Medicaid or no insurance. METHODS: A retrospective analysis performed through the National Cancer Database examined women who underwent PMR and were uninsured or had Medicaid, private insurance, or Medicare, and whose race/ethnicity, age, and state expansion status were known. Trends in the use of PMR after passage of Medicaid expansion in 2014 were evaluated. RESULTS: In all states and at all time periods, patients with private insurance were about twice as likely to undergo PMR as patients who had Medicaid or no insurance. In 2016, only 28.7 % of patients with Medicaid or no insurance in nonexpansion states underwent PMR (p < 0.001) compared with 38.5 % of patients in expansion states (p < 0.001). Patients in expansion states also have higher levels of education, higher income, and greater likelihood of living in metropolitan areas. Additionally, patients in all states saw an increase in early-stage disease, with a concomitant reduction in late disease, but this change was greater in expansion states than in non-expansion states. CONCLUSIONS: Expansion states have larger proportions of patients undergoing PMR than non-expansion states. This difference stems from significant differences in income, education, comorbidities, race, and location. Large metropolitan areas have the largest number of patients undergoing PMR, whereas rural areas have the least.

Apocrine Breast Cancer: Unique Features of a Predominantly Triple-Negative Breast Cancer.

INTRODUCTION: Invasive apocrine carcinoma is a rare breast cancer that is frequently triple negative. Little is known about the characteristics of its molecular subtypes. We compared the incidence, demographics, and clinicopathologic features of this cancer with non-apocrine carcinomas stratified by molecular subtype. METHODS: Women with invasive apocrine cancer were retrospectively identified from the Surveillance, Epidemiology, and End Results (SEER) database. Clinicopathologic and demographic features were compared with non-apocrine carcinomas, both overall using data from 2004 to 2017 and stratified by molecular subtypes using data from 2010 to 2017. The life table method was used to determine the 7-year breast cancer-specific survival. RESULTS: Compared with non-apocrine cancers, apocrine cancers presented at a younger age, with larger, higher-grade tumors that were much more likely to be triple negative (50% vs. 11%) or human epidermal growth factor receptor 2 (HER2)-positive (28% vs. 15%) and less likely to be luminal (22% vs. 74%); however, the 7-year survival was the same at 85%. The characteristics varied dramatically by molecular type. Compared with non-apocrine triple-negative, apocrine triple-negative patients were less likely to be African American and were much older, with smaller, lower-grade tumors and much better survival (86% vs. 74%). In contrast, compared with luminal non-apocrine, apocrine luminal patients had larger, higher-grade tumors and worse survival (79% vs. 89%). CONCLUSIONS: Invasive apocrine carcinomas have more aggressive features than non-apocrine carcinomas but the breast cancer-specific survival is the same. Half of these apocrine tumors are triple negative but these have more favorable features and much better survival than non-apocrine triple-negative cancers.

Assessing Interobserver Variability of Cosmetic Outcome Assessment in Breast Cancer Patients Undergoing Breast-Conservation Surgery.

BACKGROUND: Inter-rater reliability between breast surgical oncologists and reconstructive surgeons using cosmesis scales, and the correlation between their observations and patients' own subjective assessments, is poorly understood. METHODS: Patients undergoing BCS in a prospective trial rated their cosmetic outcome on a Likert scale (poor/fair/good/excellent) at the postoperative and 1-year time points; photographs were also taken. Three breast surgical oncologists (not involved in these cases) and two reconstructive surgeons were asked to independently rate cosmesis using the Harvard/NSABP/RTOG scale. RESULTS: Overall, 55 and 17 patients had photographs and Likert self-evaluations at the postoperative and 1-year time points, respectively. There was poor agreement between surgeon and patient ratings postoperatively [kappas - 0.042 (p = 0.659), 0.069 (p = 0.226), and 0.076 (p = 0.090) for the breast surgical oncologists; and 0.018 (p = 0.689) and 0.112 (p = 0.145) for the reconstructive surgeons], and poor interobserver agreement between surgeons of the same specialty (kappa - 0.087, 95% confidence interval [CI] - 0.091 to - 0.082, p = 0.223 for breast surgical oncologists; and kappa - 0.150, 95% CI - 0.157 to - 0.144, p = 0.150, for reconstructive surgeons). At 1 year, the interobserver agreement between breast surgical oncologists was better (kappa 0.507, 95% CI 0.501-0.512, p < 0.001); however, there was still poor correlation between the reconstructive surgeons (kappa - 0.040, 95% CI - 0.049 to - 0.031, p = 0.772). Agreement between surgeon and patient ratings remained poor at this time point [kappas - 0.115 (p = 0.477), 0.177 (p = 0.245), and 0.101 (p = 0.475) for breast surgical oncologists; and 0.335 (p = 0.037) and -0.118 (p = 0.221) for reconstructive surgeons]. CONCLUSION: Despite gradation scales for measuring cosmesis after BCS, high levels of agreement between surgeons is lacking and these do not always reflect patients' subjective assessments.

Characteristics and Long-Term Risk of Breast Angiosarcoma.

BACKGROUND: Angiosarcoma of the breast is rare and aggressive. It can occur as a de novo tumor or secondary to breast cancer treatment. The purpose of this study is to analyze differences between patients with primary and secondary angiosarcoma of the breast and investigate potential risk factors for its development. PATIENTS AND METHODS: The Surveillance, Epidemiology, and End Results program of the National Cancer Institute database was queried to identify patients with angiosarcoma of the breast, trunk, shoulder, and upper arm. The population-based incidence was analyzed. Primary and secondary angiosarcoma cases were identified and compared. Breast cancer characteristics of secondary angiosarcoma patients were compared with all breast cancer patients in the database who did not develop angiosarcoma. RESULTS: Overall, 904 patients were included, and 65.4% were secondary angiosarcomas. These patients had worse survival, were older, more likely to be White, more likely to have regionally advanced disease, and had angiosarcoma tumors of higher pathologic grade. Independent factors associated with development of secondary angiosarcoma among breast cancer patients included White race, older age, invasive tumor, lymph node removal, lumpectomy, radiation treatment, and left-sided tumor. Although the mean time to develop angiosarcoma after breast cancer diagnosis was 8.2 years, the risk continues to increase up to 30 years after breast cancer treatment. CONCLUSION: Angiosarcoma is rare but increasing in incidence. Secondary angiosarcomas are more common and exhibit more aggressive behavior. Several factors for angiosarcoma after breast cancer treatment could be identified, which may help us counsel and identify patients at risk.

Neoadjuvant durvalumab plus weekly nab-paclitaxel and dose-dense doxorubicin/cyclophosphamide in triple-negative breast cancer.

The goal of this Phase I/II trial is to assess the safety and efficacy of administering durvalumab concurrent with weekly nab-paclitaxel and dose-dense doxorubicin/cyclophosphamide (ddAC) neoadjuvant therapy for stages I-III triple-negative breast cancer. The primary endpoint is pathologic complete response (pCR:ypT0/is, ypN0). The response was correlated with PDL1 expression and stromal tumor-infiltrating lymphocytes (sTILs). Two dose levels of durvalumab (3 and 10 mg/kg) were assessed. PD-L1 was assessed using the SP263 antibody; ≥1% immune and tumor cell staining was considered positive; sTILs were calculated as the area occupied by mononuclear inflammatory cells over the total intratumoral stromal area. 59 patients were evaluable for toxicity and 55 for efficacy in the Phase II study (10 mg/kg dose). No dose-limiting toxicities were observed in Phase I. In Phase II, pCR rate was 44% (95% CI: 30-57%); 18 patients (31%) experienced grade 3/4 treatment-related adverse events (AE), most frequently neutropenia (n = 4) and anemia (n = 4). Immune-related grade 3/4 AEs included Guillain-Barre syndrome (n = 1), colitis (n = 2), and hyperglycemia (n = 2). Of the 50 evaluable patients for PD-L1, 31 (62%) were PD-L1 positive. pCR rates were 55% (95% CI: 0.38-0.71) and 32% (95% CI: 0.12-0.56) in the PD-L1 positive and negative groups (p = 0.15), respectively. sTIL counts were available on 52 patients and were significantly higher in the pCR group (p = 0.0167). Concomitant administration of durvalumab with sequential weekly nab-paclitaxel and ddAC neoadjuvant chemotherapy resulted in a pCR rate of 44%; pCR rates were higher in sTIL-high cancers.

Surgical Outcomes of Mastectomy with Immediate Autologous Reconstruction Followed by Radiation.

INTRODUCTION: Timing of autologous reconstruction relative to postmastectomy radiation therapy (PMRT) is debated. Benefits of immediate reconstruction must be weighed against a possibly heightened risk of complications from flap irradiation. We reviewed flap outcomes after single operation plus PMRT in a large institutional cohort. METHODS: Medical records were reviewed for women who underwent simultaneous mastectomy-autologous reconstruction with PMRT from 2007 to 2016. Primary endpoints were rates and types of radiation-related flap complications and reoperations, whose predictors were assessed by multivariable analysis. A p value < 0.10 was deemed significant to avoid type II error. Non-parametric logistic regression generated a model of PMRT timing associated with probabilities of complications and reoperations. RESULTS: One-hundred and thirty women underwent 208 mastectomy reconstruction operations, with a median follow up of 35.1 months (interquartile range 23.6-56.5). Forty-seven (36.2%) women experienced radiation-related complications, commonly fat necrosis (44.1%) and chest wall asymmetry (28.8%). Complications were higher among women who received PMRT < 3 months after surgery (46.8% for < 3 months vs. 29.3% for ≥ 3 months; p = 0.06), most of whom received neoadjuvant chemotherapy, and among women treated with internal mammary nodal (IMN) radiation (65.2% vs. 26.4%; p < 0.01); IMN radiation remained strongly associated in multivariable analysis (odds ratio [OR] 5.24; p < 0.01). Thirty-two (24.6%) women underwent 70 reoperations, commonly fat grafting (51.9%) and fat necrosis excision (17.1%). Reoperations were higher among women who received PMRT < 3 months after surgery (48.9 for < 3 months vs. 36.6 for ≥ 3 months; p = 0.19), which was significantly associated in multivariable analysis (OR 0.42; p = 0.08 for ≥ 3 months). The probabilities of complications and reoperations were lowest when PMRT was administered ≥ 3 months after surgery. CONCLUSIONS: Among a large institutional cohort, immediate autologous reconstruction was associated with similar rates of adverse flap outcomes as historically reported alternatively sequenced protocols. IMN radiation increased risk, while PMRT ≥ 3 months after surgery decreased risk. Additional studies are needed to elaborate the impact of IMN radiation and early PMRT in immediate versus delayed autologous reconstruction.

Association of Medicaid Expansion Under the Affordable Care Act With Breast Cancer Stage at Diagnosis.

Importance: The expansion of Medicaid sought to fill gaps in insurance coverage among low-income Americans. Although coverage has improved, little is known about the relationship between Medicaid expansion and breast cancer stage at diagnosis. Objective: To review the association of Medicaid expansion with breast cancer stage at diagnosis and the disparities associated with insurance status, age, and race/ethnicity. Design, Setting, and Participants: This cohort study used data from the National Cancer Database to characterize the relationship between breast cancer stage and race/ethnicity, age, and insurance status. Data from 2007 to 2016 were obtained, and breast cancer stage trends were assessed. Additionally, preexpansion years (2012-2013) were compared with postexpansion years (2015-2016) to assess Medicaid expansion in 2014. Data were analyzed from August 12, 2019, to January 19, 2020. The cohort included a total of 1 796 902 patients with primary breast cancer who had private insurance, Medicare, or Medicaid or were uninsured across 45 states. Main Outcomes and Measures: Percent change of uninsured patients with breast cancer and stage at diagnosis, stratified by insurance status, race/ethnicity, age, and state. Results: This study included a total of 1 796 902 women. Between 2012 and 2016, 71 235 (4.0%) were uninsured or had Medicaid. Among all races/ethnicities, in expansion states, there was a reduction in uninsured patients from 22.6% (4771 of 21 127) to 13.5% (2999 of 22 150) (P < .001), and in nonexpansion states, there was a reduction from 36.5% (5431 of 14 870) to 35.6% (4663 of 13 088) (P = .12). Across all races, there was a reduction in advanced-stage disease from 21.8% (4603 of 21 127) to 19.3% (4280 of 22 150) (P < .001) in expansion states compared with 24.2% (3604 of 14 870) to 23.5% (3072 of 13 088) (P = .14) in nonexpansion states. In African American patients, incidence of advanced disease decreased from 24.6% (1017 of 4136) to 21.6% (920 of 4259) (P < .001) in expansion states and remained at approximately 27% (27.4% [1220 of 4453] to 27.5% [1078 of 3924]; P = .94) in nonexpansion states. Further analysis suggested that the improvement was associated with a reduction in stage 3 diagnoses. Conclusions and Relevance: In this cohort study, expansion of Medicaid was associated with a reduced number of uninsured patients and a reduced incidence of advanced-stage breast cancer. African American patients and patients younger than 50 years experienced particular benefit. These data suggest that increasing access to health care resources may alter the distribution of breast cancer stage at diagnosis.

Management of recurrent bilateral multifocal pseudoangiomatous stromal hyperplasia (PASH).

Pseudoangiomatous stromal hyperplasia (PASH) is a benign hyperplastic condition of the breast that can lead to macromastia. The standard treatment for PASH is focal excision or rarely reduction mammoplasty. We present a rare case of postpartum bilateral rapid breast enlargement and axillary growth that was refractory to reduction mammoplasty. Ultimately, the patient required bilateral mastectomy and two-stage implant-based breast reconstruction. This more extensive form along with its management represents one of the few reported cases in the literature. The decision to pursue bilateral mastectomy was undertaken after exhausting more conservative options. Excellent aesthetic outcome and pain relief was obtained following definitive extirpative and reconstructive surgery.

Systematic Immunotherapy Target Discovery Using Genome-Scale In Vivo CRISPR Screens in CD8 T Cells.

CD8 T cells play essential roles in anti-tumor immune responses. Here, we performed genome-scale CRISPR screens in CD8 T cells directly under cancer immunotherapy settings and identified regulators of tumor infiltration and degranulation. The in vivo screen robustly re-identified canonical immunotherapy targets such as PD-1 and Tim-3, along with genes that have not been characterized in T cells. The infiltration and degranulation screens converged on an RNA helicase Dhx37. Dhx37 knockout enhanced the efficacy of antigen-specific CD8 T cells against triple-negative breast cancer in vivo. Immunological characterization in mouse and human CD8 T cells revealed that DHX37 suppresses effector functions, cytokine production, and T cell activation. Transcriptomic profiling and biochemical interrogation revealed a role for DHX37 in modulating NF-κB. These data demonstrate high-throughput in vivo genetic screens for immunotherapy target discovery and establishes DHX37 as a functional regulator of CD8 T cells.

The impact of communication style on patient satisfaction.

BACKGROUND: Communication between patients and health providers influences patient satisfaction, but it is unknown whether similarity in communication styles results in higher patient satisfaction. METHODS: This study was conducted in the Smilow Cancer Hospital Breast Center. During routine follow-up visits, patients completed a Communication Styles Assessment (CSA), health survey (SF-12), Princess Margaret Hospital Satisfaction with Doctor Questionnaire, and brief demographic form. Physicians and Advanced Practice Providers were also asked to complete the CSA. Patients and providers were blinded to each other's responses. A communication styles concordance score was calculated as the Pearson correlation between 80 binary CSA items for each provider/patient pair. Factors affecting patient satisfaction scores were assessed in mixed-effects models. RESULTS: In total, 330 patients were invited to participate; of these 289 enrolled and 245 returned surveys. One hundred seventy-four completed all survey components, and 18 providers completed the CSA. Among the factors considered, physical health score (effect size = 0.0058, 95% CI 0.00051 to 0.0011, p = 0.032) and employment status (0.12, 95% CI - 0.0094 to 0.25, p = 0.069) had the greatest impact on patient satisfaction. However, patients who were not employed and less physically healthy had significantly elevated satisfaction scores when their communication style was more similar to their provider's (1.52, 95% CI 0.66 to 2.38, p = 0.0016). CONCLUSIONS: Patients who were physically healthy and employed were generally more satisfied with their care. The similarity in communication styles of patients and providers had a greater impact on patient satisfaction for patients who were less physically healthy and not employed.

Why Has Breast Cancer Screening Failed to Decrease the Incidence of de Novo Stage IV Disease?

: Background: Despite screening mammography, the incidence of Stage IV breast cancer (BC) at diagnosis has not decreased over the past four decades. We previously found that many BCs are small due to favorable biology rather than early detection. This study compared the biology of Stage IV cancers with that of small cancers typically found by screening. Methods: Trends in the incidence of localized, regional, and distant female BC were compared using SEER*Stat. The National Cancer Database (NCDB) was then queried for invasive cancers from 2010 to 2015, and patient/disease variables were compared across stages. Biological variables including estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (Her2), grade, and lymphovascular invasion were sorted into 48 combinations, from which three biological subtypes emerged: indolent, intermediate, and aggressive. The distributions of the subtypes were compared across disease stages. Multivariable regression assessed the association between Stage IV disease and biology. Results: SEER*Stat confirmed that the incidence of distant BC increased between 1973 and 2015 (annual percent change [APC] = 0.46). NCDB data on roughly 993,000 individuals showed that Stage IV disease at presentation is more common in young, black, uninsured women with low income/education and large, biologically aggressive tumors. The distribution of tumor biology varied by stage, with Stage IV disease including 37.6% aggressive and 6.0% indolent tumors, versus sub-centimeter Stage I disease that included 5.1% aggressive and 40.6% indolent tumors (p < 0.001). The odds of Stage IV disease presentation more than tripled for patients with aggressive tumors (OR3.2, 95% CI 3.0⁻3.5). Conclusions: Stage I and Stage IV breast cancers represent very different populations of biologic tumor types. This may explain why the incidence of Stage IV cancer has not decreased with screening.