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In the absence of histological criteria that distinguish between inflammatory and non-inflammatory breast cancer, diagnosis of inflammatory breast cancer relies entirely on the existence of clinical criteria as outlined by the TNM classification. This classification restricts patients presenting with clinical criteria characteristic of inflammatory breast cancer to subcategory T4d, which immediately relegates all patients with non-metastatic inflammatory breast cancer to stage 3, regardless of tumour size or nodal spread. Patients who present with metastatic disease are consigned to stage 4, and the TNM classification does not distinguish patients on the basis of the presence of inflammatory criteria. Evidence by our group and others suggests that patients with inflammatory breast cancer have significantly reduced overall survival among those who present with distant metastasis at diagnosis (stage 4). In light of these results, this Personal View addresses whether the current TNM staging classification accurately represents a distinction between patients with inflammatory and those with non-inflammatory breast cancer.

Background BRCA‐associated breast cancers tend to have distinctive features compared to sporadic breast cancers; further characterization can aid in optimizing treatment. Methods The study evaluated a patient cohort with early‐stage estrogen receptor positive, HER2 negative invasive breast cancer who had Oncotype DX Breast Recurrence Score® analysis and genetic testing for hereditary breast and ovarian cancer syndrome. Data on patients and their breast cancers with outcomes were collected and analyzed. Results 745 patients were included, of whom 33 had pathogenic BRCA mutations (8 BRCA1, 25 BRCA2). Patients with BRCA mutations were younger and received more adjuvant chemotherapy, but less endocrine therapy and radiation therapy. BRCA‐associated breast cancers had less progesterone receptor expression, higher nuclear grade, and higher Oncotype DX Breast Recurrence Scores® with median Recurrence Score® 29, compared to 16 in cancers without mutations (p < 0.0001). Breast cancer recurrence developed in 18% of patients with BRCA mutations and 9% of patient without mutations, although multivariate analysis of relapse‐free survival was not significant, HR 1.519 (95% confidence interval [CI] 0.64–3.58; p = 0.3401). After adjusting for Recurrence Score®, overall survival by BRCA status was improved HR 0.448 (95% CI 0.06–3.34; p = 0.4333). Conclusions BRCA‐associated early‐stage hormone receptor‐positive breast cancers have higher Oncotype DX Breast Recurrence Score® compared to those without mutations. BRCA status did not significantly impact relapse‐free survival and overall survival. Larger clinical trials are needed to further assess the findings, and if confirmed, could impact clinical management of BRCA‐associated breast cancers. The study evaluated a patient cohort with early‐stage estrogen receptor positive, HER2‐negative invasive breast cancer who had Oncotype DX Breast Recurrence Score® analysis and genetic testing for hereditary breast and ovarian cancer syndrome. BRCA‐associated breast cancers had less progesterone receptor expression, higher nuclear grade, and higher Oncotype DX Breast Recurrence Scores® with median Recurrence Score® 29, compared to 16 in cancers without mutations (p < 0.0001). After adjusting for Recurrence Score®, overall survival by BRCA status was improved HR 0.448 (95% CI 0.06–3.34; p = 0.4333).

Health care providers need simple tools to identify patients at genetic risk of breast and ovarian cancers. Genetic risk prediction models such as BRCAPRO could fill this gap if incorporated into Electronic Medical Records or other Health Information Technology solutions. However, BRCAPRO requires potentially extensive information on the counselee and her family history. Thus, it may be useful to provide simplified version(s) of BRCAPRO for use in settings that do not require exhaustive genetic counseling. We explore four simplified versions of BRCAPRO, each using less complete information than the original model. BRCAPROLYTE uses information on affected relatives only up to second degree. It is in clinical use but has not been evaluated. BRCAPROLYTE-Plus extends BRCAPROLYTE by imputing the ages of unaffected relatives. BRCAPROLYTE-Simple reduces the data collection burden associated with BRCAPROLYTE and BRCAPROLYTE-Plus by not collecting the family structure. BRCAPRO-1Degree only uses first-degree affected relatives. We use data on 2,713 individuals from seven sites of the Cancer Genetics Network and MD Anderson Cancer Center to compare these simplified tools with the Family History Assessment Tool (FHAT) and BRCAPRO, with the latter serving as the benchmark. BRCAPROLYTE retains high discrimination; however, because it ignores information on unaffected relatives, it overestimates carrier probabilities. BRCAPROLYTE-Plus and BRCAPROLYTE-Simple provide better calibration than BRCAPROLYTE, so they have higher specificity for similar values of sensitivity. BRCAPROLYTE-Plus performs slightly better than BRCAPROLYTE-Simple. The Areas Under the ROC curve are 0.783 (BRCAPRO), 0.763 (BRCAPROLYTE), 0.772 (BRCAPROLYTE-Plus), 0.773 (BRCAPROLYTE-Simple), 0.728 (BRCAPRO-1Degree), and 0.745 (FHAT). The simpler versions, especially BRCAPROLYTE-Plus and BRCAPROLYTE-Simple, lead to only modest loss in overall discrimination compared to BRCAPRO in this dataset. Thus, we conclude that simplified implementations of BRCAPRO can be used for genetic risk prediction in settings where collection of complete pedigree information is impractical.

Obese and overweight women have an increased risk of breast cancer and worse outcomes at the time of diagnosis. Women tend to gain weight after breast cancer diagnosis and during chemotherapy for early‐stage disease, which may in turn increase risk for worse outcomes. We examined if weight gained during adjuvant chemotherapy was associated with worse survival outcomes. We queried our database for data on patients who received adjuvant third‐generation chemotherapy for early‐stage breast cancer. Univariate and multivariate analyses by Cox regression were performed for survival outcomes across three categories according to BMI variation from start to end of chemotherapy: >0.5 kg/m2 loss or gain and stable BMI (±0.5 kg/m2). We included 1998 patients in this study. Women over 50 years old and postmenopausal were more likely to lose weight during adjuvant chemotherapy, whereas women under 30 years old gained more weight (P < 0.001). At 1 year postchemotherapy, patients tended to return to their original weight (ρ = −0.3, P < 0.001). On multivariate analysis, BMI increase of >0.5 kg/m2 compared to maintaining BMI was marginally associated with increased locoregional recurrence risk (HR: 2.53; 95% CI, 1.18–5.45; P = 0.017), adjusting for grade, stage, and radiation delivery. Weight variation during adjuvant chemotherapy for early‐stage breast cancer may occur as both weight gain and weight loss in a balanced manner. Furthermore, this variation seems to be transient in nature and does not appear to significantly influence recurrence rates and overall survival. Weight variation during adjuvant chemotherapy for early stage breast cancer may occur as both weight gain and weight loss in a balanced manner. Furthermore, this variation seems to be transient in nature and does not appear to significantly influence recurrence rates and overall survival.

PARP inhibitors are considered promising anti-cancer agents and currently being tested in clinical trials in hereditary breast cancer patients harboring mutations in BRCA1 and BRCA2 genes. In this study, we investigated the antiproliferative effects and mechanism of PARP inhibitors ABT-888 (Veliparib), BSI-201 (Iniparib) and AZD228 (Olaparib) in breast cancer cell lines with BRCA1 or BRCA2 mutations and 9 different BRCA wild-type cell lines with BRCA1 allelic loss. We found that AZD2281 was the most potent in the PARP inhibitors and induces significant growth inhibition (~95%) in BRCA1 mutant (HCC-1937, MDA-MB-436, and SUM-149PT) and BRCA2 mutant (HCC-1428) cell lines. AZD2281 treatment also resulted in growth inhibition ranging from 20 to 50% in cells with BRCA1 allelic loss, including ER(+), HER2/Neu(+) and triple-negative breast cancer (TNBC) cells, but showed no effect in cells without with type BRCA without allelic loss. Knocking down of BRCA1 or BRCA2 in TNBC cells with BRCA1 allelic loss by RNA interference significantly enhanced AZD2281-induced growth inhibition and induced significant autophagy that was associated with mitophagy in cells with BRCA mutations. Inhibition of autophagy by gene knockdown significantly diminished AZD2281-induced mitophagy and apoptosis, indicating that autophagic process mediates some of the downstream effects of PARP inhibitors. In conclusion, our data provide the first evidence of PARP inhibitor AZD2281 autophagy and mitophagy in breast cancer cell lines with BRCA mutations or BRCA-allelic loss. In addition, our results indicate that the patients with BRCA1 allelic loss may also benefit from PARP inhibitor therapy if BRCA is further inhibited.

Although multigene panel testing is increasingly common in patients with cancer, the relationship between its use among breast cancer patients with non‐BRCA mutations or variants of uncertain significance (VUS) and disease management decisions has not been well described. This study evaluated the rate and predictive factors of CPM patients who underwent multigene panel testing. Three hundred and fourteen patients with breast cancer who underwent multigene panel testing between 2014 and 2017 were included in the analysis. Of the 314 patients, 70 elected CPM. Election of CPM by gene status was as follows: BRCA carriers (42.3%), non‐BRCA carriers (30.1%), and VUS (10.6%). CPM election rates did not differ between non‐BRCA carriers and BRCA carriers (P = 0.6205). Among non‐BRCA carriers, negative hormone receptor status was associated with CPM (P = 0.0115). For those with a VUS, hormone receptor status was not associated with CPM (P = 0.1879). Although the rate of CPM between BRCA carriers and non‐BRCA carriers was not significantly different, the predictors of CPM were different in each group. Our analyses shed the light on the increasing use of CPM among patients who are non‐BRCA carriers as well those with a VUS. Our study elucidates the differing predictive factors of CPM election among BRCA carriers, non‐BRCA carries, and those with a VUS. Our findings reveal the need for providers to be cognizant that non‐BRCA genes and VUS drive women to elect CPM despite the lack of data for contralateral breast cancer risk associated with these genes. We evaluated CPM rates and predictive factors among patients who underwent multigene panel testing. Overall, 23% of patients with breast cancer who underwent multigene panel testing, including BRCA carriers, non‐BRCA carriers, and those with a VUS, opted for CPM. Patients who had a pathogenic variant in BRCA1 or BRCA2 or another, non‐BRCA gene were more likely to elect CPM than those with a VUS, no matter which gene was implicated. Although the rate of CPM between BRCA carriers and non‐BRCA carriers was not significantly different, the predictors of CPM were different in each group.

Background Women with a history of breast cancer (BC) more commonly have a diagnosis of other primary malignancies (OPMs) than the general population. This study sought to evaluate OPMs among patients with BC who underwent germline testing with a hereditary BC gene panel. Methods The study identified women 18 years of age or older with a history of unilateral BC who underwent multi-gene panel testing between January 2014 and August 2019 at the authors’ institution. Patient, tumor, and treatment factors for BC and OPM diagnoses were collected for descriptive, univariate, and overall survival (OS) analyses. Results Among 1163 patients, 330 (28.4%) had an OPM. The median follow-up period was 4.1 years from BC diagnosis. Of the 1163 patients, 209 (18%) had a BRCA pathogenic variant (PV), 306 (26.4%) had a non- BRCA PV, and 648 (55.7%) had no PV. Development of an OPM varied according to germline testing result, with an OPM developing for 18.6% (39/209) of the patients with a BRCA PV, 31.8% (204/648) of the patients with no PV, and 28.4% (87/306) of the patients with a non- BRCA PV ( p < 0.0001). The most common OPMs were ovarian ( n = 60), uterine ( n = 44), sarcoma ( n = 36), melanoma ( n = 27), colorectal ( n = 22), and lymphoma ( n = 20) malignancies. The 5-year OS was 96%. The patients with an OPM 5 years after BC diagnosis had a shorter OS than those who did not (93.4% vs 97.5%; p = 0.002). Conclusion More than 25% of women with BC who underwent germline panel testing had an OPM diagnosed during the short-term follow-up period, and the diagnosis of an OPM was associated with reduced OS. These data have implications for counseling BC patients who undergo germline testing regarding future cancer screening.

Abstract Background Limited published literature exists on women with triple-negative breast cancer (TNBC) diagnosed over the age of 60 years with breast cancer gene (BRCA) pathogenic variants. Our study determined whether the rate of BRCA pathogenic variants in a prospective cohort of TNBC patients outside the definition of current clinical genetic testing (GT) guidelines warrants a change in recommendations. Methods A prospective study of 395 women with TNBC underwent genetic counseling and 380 (96.2%) underwent clinical BRCA GT regardless of age of diagnosis beginning January 2014 to October 2015 at The University of Texas MD Anderson Cancer Center, Houston. TNBC patients older than 60 years who did not meet clinical GT guidelines had comprehensive sequencing and large rearrangement GT as part of the research protocol. Results Fifty-one of 380 (13.4%) women with TNBC who underwent clinical BRCA GT were BRCA positive. Of the 86 patients diagnosed at age over 60 years and underwent GT, only two (2.3%) were positive for BRCA. These two patients would have met clinical testing criteria due to family or ancestral history. Conclusions Our study does not support universal BRCA testing for TNBC patients diagnosed older than 60 years as their only risk factor for a BRCA pathogenic variant. Both of the positive BRCA patients older than 60 years identified would have met current National Comprehensive Cancer Network criteria for testing. Therefore, our study demonstrates that the National Comprehensive Cancer Network guidelines provide sufficient criteria for identifying BRCA pathogenic variants in women with TNBC at 60 years or younger.

Background. Patients with unilateral breast cancer carrying pathogenic variants in BRCA1/2 have the option to undergo contralateral prophylactic mastectomy (CPM). However, differences in CPM use and survival outcomes following CPM are poorly understood in this high-risk population, in part due to a lack of data from contemporary clinical cohorts. The objective of this study was to evaluate post-CPM overall survival (OS) and related racial/ethnic differences in a contemporary clinical cohort. Methods. We retrospectively reviewed the medical records of women with a personal history of unilateral breast cancer carrying pathogenic variants in BRCA1/2 who were diagnosed between 1996 and 2012. Genetic test results, self-reported demographic characteristics, and clinical factors were abstracted from electronic medical records. Results. Of 144 BRCA-positive patients, the majority were White (79.2%, n = 114). Overall, 56.1% (n = 81) of all BRCA1/2 carriers chose to undergo CPM, with no racial/ethnic difference in CPM election (p = 0.78). Of 81 patients who underwent CPM, there is strong evidence of a difference in survival between the racial/ethnic groups, with White patients having the highest OS compared to non-White patients (p = 0.001). Of the 63 patients who did not undergo CPM, there is no racial/ethnic difference in overall survival (p = 0.61). In multivariable cox regression, adjusted for demographic and clinical characteristics, OS was significantly lower among non-Whites than in Whites (HR = 0.39, p = 0.04). Conclusions. Evaluation of a contemporary clinical cohort of BRCA-positive women with unilateral breast cancer showed no racial/ethnic difference in CPM use, but there was a significant difference in post-CPM overall survival.

Purpose The carbohydrate sialyl Lewis X (sLe X ) mediates cell adhesion, is critical in the normal function of immune cells, and is frequently over-expressed on cancer cells. We assessed the association, differential levels, and prognostic value of sLe X and inflammatory cytokines/chemokines in breast cancer sera. Methods We retrospectively measured sLe X and a panel of cytokines/chemokines in the sera of 26 non-invasive ductal carcinoma in situ (DCIS), 154 invasive non-metastatic breast cancer (non-MBC), 63 metastatic breast cancer (MBC) patients, and 43 healthy controls. Differences in sLe X and inflammatory cytokines among and between patient groups and healthy controls were assessed with nonparametric tests and we performed survival analysis for the prognostic potential of sLe X using a cut-off of 8 U/mL as previously defined. Results Median serum sLe X was significantly higher than controls for invasive breast cancer patients (MBC and non-MBC) but not DCIS. In univariate analysis, we confirmed patients with serum sLe X  > 8 U/mL have a significantly shorter progression-free survival (PFS) ( P  = 0.0074) and overall survival (OS ( P  = 0.0003). Similarly, patients with high serum MCP-1 and IP-10 had shorter OS ( P  = 0.001 and P  < 0.001, respectively) and PFS ( P  = 0.010 and P  < 0.001, respectively). sLe X , MCP-1 and IP-10 remained significant in multivariate survival analysis. Conclusion Elevated serum sLe X was associated with invasive cancer but not DCIS. High serum sLe X levels were associated with inflammatory mediators and may play a role in facilitating local invasion of breast tumor. Furthermore, serum MCP-1, IP-10 and sLe X may have prognostic value in breast cancer.