Validating risk prediction models for multiple primaries and competing cancer outcomes in families with Li-Fraumeni syndrome using clinically ascertained data at a single institute.

Purpose: There exists a barrier between developing and disseminating risk prediction models in clinical settings. We hypothesize this barrier may be lifted by demonstrating the utility of these models using incomplete data that are collected in real clinical sessions, as compared to the commonly used research cohorts that are meticulously collected. Patients and methods: Genetic counselors (GCs) collect family history when patients (i.e., probands) come to MD Anderson Cancer Center for risk assessment of Li-Fraumeni syndrome, a genetic disorder characterized by deleterious germline mutations in the TP53 gene. Our clinical counseling-based (CCB) cohort consists of 3,297 individuals across 124 families (522 cases of single primary cancer and 125 cases of multiple primary cancers). We applied our software suite LFSPRO to make risk predictions and assessed performance in discrimination using area under the curve (AUC), and in calibration using observed/expected (O/E) ratio. Results: For prediction of deleterious TP53 mutations, we achieved an AUC of 0.81 (95% CI, 0.70 - 0.91) and an O/E ratio of 0.96 (95% CI, 0.70 - 1.21). Using the LFSPRO.MPC model to predict the onset of the second cancer, we obtained an AUC of 0.70 (95% CI, 0.58 - 0.82). Using the LFSPRO.CS model to predict the onset of different cancer types as the first primary, we achieved AUCs between 0.70 and 0.83 for sarcoma, breast cancer, or other cancers combined. Conclusion: We describe a study that fills in the critical gap in knowledge for the utility of risk prediction models. Using a CCB cohort, our previously validated models have demonstrated good performance and outperformed the standard clinical criteria. Our study suggests better risk counseling may be achieved by GCs using these already-developed mathematical models.

Other Primary Malignancies in Patients with Breast Cancer Who Undergo Germline Panel Testing.

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.

Aromatase inhibitors and contralateral breast cancer in BRCA mutation carriers.

BACKGROUND: Deleterious BRCA mutations confer a significant lifetime risk of breast cancer (BC) as well as contralateral BC (CBC) in patients who do not undergo prophylactic mastectomy. Prior reports have suggested that tamoxifen reduces the risk of CBC in BRCA mutation carriers. Whether aromatase inhibitors (AI) have the same effect is unknown. METHODS: This is a retrospective review of patients diagnosed with non-metastatic ER+ BC between 2004 and 2014 with known BRCA mutation status. Patients were followed from primary diagnosis until CBC diagnosis or death. Median follow-up was 11.5 years. Risk of CBC was evaluated as time to event. RESULTS: 935 subjects were included in this analysis, with 53 BRCA1 mutation carriers, and 94 BRCA2 mutation carriers. Median age at diagnosis was 42.7 years. Seventy-two percent (676) received tamoxifen and 43% (405) received AI. A total of 66 CBCs occurred, of which 10% (15/147) occurred in BRCA mutation carriers vs 6.5% (51/788) in BRCA wild type. Multivariate analyses indicated that BRCA status and AI use were significantly associated with CBC risk. AI use resulted in a significant reduction in risk of CBC (HR 0.44, p = 0.004) regardless of the BRCA mutation status. Tamoxifen use was not associated with reduced risk of CBC. CONCLUSIONS: This is the first report showing that AIs reduce the risk of CBC in BRCA mutation carriers. The potential role of AIs as chemoprevention should be validated in larger independent cohorts.

Incidence and impact of brain metastasis in patients with hereditary BRCA1 or BRCA2 mutated invasive breast cancer.

Patients with hereditary mutations in BRCA1 or BRCA2 (gBRCA1/2) and breast cancer have distinct tumor biology, and encompass a predilection for brain metastasis (BM). We looked into baseline risk of BMs among gBRCA1/2 patients. Patients with gBRCA1/2, stage I-III invasive breast cancer seen between 2000-2017 with parenchymal BMs. Among gBRCA1 with distant breast cancer recurrence, 34 of 76 (44.7%) were diagnosed with brain metastases compared to 7 of 42 (16.7%) patients with gBRCA2. In the comparator group, 65 of 182 (35.7%) noncarrier triple-negative breast cancer (TNBC) and a distant recurrence experienced BM's. In a competitive risk analysis using death as a competing factor, the cumulative incidence of BMs was similar between gBRCA1 and noncarrier TNBC patients. The time from primary breast cancer diagnosis to detection of BMs was similar between gBRCA1 and noncarrier TNBC patients (2.4 vs 2.2 years). Survival was poor after BMs (7.8 months for gBRCA1 patients vs. 6.2 months for TNBC noncarriers). Brain was a more common site of initial distant recurrence in gBRCA1 patients versus TNBC noncarriers (26.3% vs. 12.1%). Importantly, the presence of BMs, adversely impacted overall survival across groups (HR 1.68 (95% CI 1.12-2.53), hazard ratio for death if a patient had BMs at the time of initial breast cancer recurrence vs. not). In conclusion, breast cancer BMs is common and is similarly frequent among gBRCA1 and noncarrier patients with recurrent TNBC. Our study highlights the importance of improving the prevention and treatment of BMs in patients with TNBC, gBRCA1 carriers, and noncarriers.

Clinical outcomes and Oncotype DX Breast Recurrence Score® in early-stage BRCA-associated hormone receptor-positive 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.

Validation of medical prescriptions' suitability on patients with heart disease / Validación de la idoneidad de la prescripción médica en pacientes cardiópatas.

Objective: Give pharmacotherapeutic following and study the variability and suitability of medical prescriptions given to patients during their hospitalization, through optimal and individualized pharmaceutical attention, that allows the best treatment stablished for each patient. Method: Data was captured prospectively, descriptively, and longitudinally with the purpose of analyzing the treatment's suitability in patients with heart disease, through their pharmacotherapeutic following. Results: The pharmacotherapeutic evaluation of a population of 1,228 subjects proved that elderly male patients with multiple comorbidities and in polypharmacy are more susceptible of presenting severe drug interactions (65%) and prescription errors (14.4%). Conclusions: It is essential to have a specialized pharmacist within a multi-disciplinary medical team who manages the validation of each prescription's suitability, making pharmaceutical interventions which allows the early detection of drug interactions and prescription errors, minimizing the probability of presenting real side effects and ensuring the effectiveness and security of the medical treatment.

Objetivo: Dar seguimiento farmacoterapéutico (SFT) y estudiar la variabilidad e idoneidad de la prescripción farmacológica de los pacientes durante su estancia hospitalaria, por medio de una atención farmacéutica individualizada que permita obtener mejores resultados en el tratamiento farmacológico. Método: Los datos fueron capturados de manera prospectiva, descriptiva y longitudinal para analizar la idoneidad del tratamiento, a pacientes cardiópatas, mediante el SFT. Resultados: La evaluación del SFT de población de 1,228 pacientes demostró que los pacientes cuentan con múltiples comorbilidades, polifarmacia, predominio del sexo masculino y de edad avanzada, por lo que son más propensos a presentar interacciones farmacológicas (IF) graves (65%) y errores en la medicación (14.4%). Conclusiones: Es indispensable la integración de un farmacéutico facultado en el equipo multidisciplinario de salud, que lleve a cabo la validación de la idoneidad en la prescripción médica, con una intervención farmacéutica que permita identificar oportunamente IF y errores en la medicación, disminuyendo así la probabilidad de presentar efectos reales ante la presencia de estas, asegurando la efectividad, seguridad y eficacia de los medicamentos.

Outcomes After Breast Radiation Therapy in a Diverse Patient Cohort With a Germline BRCA1/2 Mutation.

PURPOSE: BRCA1/2 pathogenic variant (PV) mutations confer radiation sensitivity preclinically, but there are limited data regarding breast cancer outcomes after radiation therapy (RT) among patients with documented BRCA1/2 PV mutations versus no PV mutations. METHODS AND MATERIALS: This retrospective cohort study included women with clinical stage I-III breast cancer who received definitive surgery and RT and underwent BRCA1/2 genetic evaluation at the The University of Texas MD Anderson Cancer Center. Rates of locoregional recurrence (LRR), disease-specific death (DSD), toxicities, and second cancers were compared by BRCA1/2 PV status. RESULTS: Of the 2213 women who underwent BRCA1/2 testing, 63% self-reported their race as White, 13.6% as Black/African American, 17.6% as Hispanic, and 5.8% as Asian/American Indian/Alaska Native; 124 had BRCA1 and 100 had BRCA2 mutations; and 1394 (63%) received regional nodal RT. The median follow-up time for all patients was 7.4 years (95% confidence interval [CI], 7.1-7.7 years). No differences were found between the groups with and without BRCA1/2 PV mutations in 10-year cumulative incidences of LRR (with mutations: 11.6% [95% CI, 7.0%-17.6%]; without mutations: 6.6% [95% CI, 5.3%-8.0%]; P = .466) and DSD (with mutations: 12.3% [95% CI, 8.0%-17.7%]; without mutations: 13.8% [95% CI, 12.0%-15.8%]; P = .716). On multivariable analysis, BRCA1/2 status was not associated with LRR or DSD, but Black/African American patients (P = .036) and Asians/American Indians/Alaska Native patients (P = .002) were at higher risk of LRR compared with White patients, and Black/African American patients were at higher risk of DSD versus White patients (P = .004). No in-field, nonbreast second cancers were observed in the BRCA1/2 PV group. Rates of acute and late grade ≥3 radiation-related toxicity in the BCRA1/2 PV group were 5.4% (n = 12) and 0.4% (n = 1), respectively. CONCLUSIONS: Oncologic outcomes in a diverse cohort of patients with breast cancer who had a germline BRCA1/2 PV mutation and were treated with RT were similar to those of patients with no mutation, supporting the use of RT according to standard indications in patients with a germline BRCA1/2 PV mutation.

Breast Radiation Therapy-Related Treatment Outcomes in Patients With or Without Germline Mutations on Multigene Panel Testing.

PURPOSE: Multigene panel testing has increased the detection of germline mutations in patients with breast cancer. The implications of using radiation therapy (RT) to treat patients with pathogenic variant (PV) mutations are not well understood and have been studied mostly in women with only BRCA1 or BRCA2 PVs. We analyzed oncologic outcomes and toxicity after adjuvant RT in a contemporary, diverse cohort of patients with breast cancer who underwent genetic panel testing. METHODS AND MATERIALS: We retrospectively reviewed the records of 286 women with clinical stage I-III breast cancer diagnosed from 1995 to 2017 who underwent surgery, breast or chest wall RT with or without regional nodal irradiation, multigene panel testing, and evaluation at a large cancer center's genetic screening program. We evaluated rates of overall survival, locoregional recurrence, disease-specific death, and radiation-related toxicities in 3 groups: BRCA1/2 PV carriers, non-BRCA1/2 PV carriers, and patients without PV mutations. RESULTS: PVs were detected in 25.2% of the cohort (12.6% BRCA1/2 and 12.6% non-BRCA1/2). The most commonly detected non-BRCA1/2 mutated genes were ATM, CHEK2, PALB2, CDH1, TP53, and PTEN. The median follow-up time for the entire cohort was 4.4 years (95% confidence interval, 3.8-4.9 years). No differences were found in overall survival, locoregional recurrence, or disease-specific death between groups (P > .1 for all). Acute and late toxicities were comparable across groups. CONCLUSION: Oncologic and toxicity outcomes after RT in women with PV germline mutations detected by multigene pane testing are similar to those in patients without detectable mutations, supporting the use of adjuvant RT as a standard of care when indicated.

Contralateral Prophylactic Mastectomy among Women with Pathogenic Variants in BRCA1/2: Overall Survival, Racial, and Ethnic Differences.

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.

Breast tumours maintain a reservoir of subclonal diversity during expansion.

Our knowledge of copy number evolution during the expansion of primary breast tumours is limited1,2. Here, to investigate this process, we developed a single-cell, single-molecule DNA-sequencing method and performed copy number analysis of 16,178 single cells from 8 human triple-negative breast cancers and 4 cell lines. The results show that breast tumours and cell lines comprise a large milieu of subclones (7-22) that are organized into a few (3-5) major superclones. Evolutionary analysis suggests that after clonal TP53 mutations, multiple loss-of-heterozygosity events and genome doubling, there was a period of transient genomic instability followed by ongoing copy number evolution during the primary tumour expansion. By subcloning single daughter cells in culture, we show that tumour cells rediversify their genomes and do not retain isogenic properties. These data show that triple-negative breast cancers continue to evolve chromosome aberrations and maintain a reservoir of subclonal diversity during primary tumour growth.

Cytoplasmic Cyclin E Expression Predicts for Response to Neoadjuvant Chemotherapy in Breast Cancer.

BACKGROUND: Pathologic complete response (pCR) has been shown to be associated with favorable outcomes in breast cancer. Predictors of pCR could be useful in guiding treatment decisions regarding neoadjuvant therapy. The objective of this study was to evaluate cyclin E as a predictor of response to neoadjuvant chemotherapy in breast cancer. METHODS: Patients (n = 285) with stage II-III breast cancer were enrolled in a prospective study and received neoadjuvant chemotherapy with anthracyclines, taxanes, or combination of the two. Pretreatment biopsies from 190 patients and surgical specimens following chemotherapy from 192 patients were available for immunohistochemical analysis. Clinical and pathologic responses were recorded and associated with presence of tumor infiltrating lymphocytes, cyclin E, adipophilin, programmed cell death-ligand 1, and elastase staining and other patient, tumor and treatment characteristics. RESULTS: The pCR rate was significantly lower in patients with cytoplasmic cyclin E staining compared with those who had no cyclin E expression (16.1% vs 38.9%, P = 0.0005). In multivariable logistic regression analysis, the odds of pCR for patients who had cytoplasmic negative tumors was 9.35 times (P value < 0.0001) that compared with patients with cytoplasmic positive tumors after adjusting for ER, PR, and HER2 status. Cytoplasmic cyclin E expression also predicts long-term outcome and is associated with reduced disease free, recurrence free, and overall survival rates, independent of increased pretreatment tumor infiltrating lymphocytes. CONCLUSIONS: Cyclin E independently predicted response to neoadjuvant chemotherapy. Hence, its routine immunohistochemical analysis could be used clinically to identify those breast cancer patients expected to have a poor response to anthracycline/taxane-based chemotherapy.

Imaging Features of Triple Negative Breast Cancer and the Effect of BRCA Mutations.

OBJECTIVE: The purpose of this study is to review the mammographic and the ultrasound features of triple negative breast cancer (TNBC) patients and to investigate the potential effect of BRCA mutations on the imaging features of these patients. METHODS: One hundred and seven patients with TNBC were enrolled in a retrospective study following IRB approval and approval of waiver of informed consent. BRCA mutations were assessed using genetic testing. Imaging features on mammography and ultrasound (US) as well as pathology and clinical information were retrospectively reviewed and characterized according to the BI-RADS lexicon (fifth edition). The relationships between BRCA mutations and the imaging findings were examined. RESULTS: TNBC commonly presented as an irregular mass with obscured margins on mammography and as an irregular hypoechoic mass with microlobulated or angular margins on US. Approximately two thirds of TNBC cases had a parallel orientation and approximately one third had posterior enhancement, features often associated with benign masses. There was no statistically significant difference in the mammographic and the US features of BRCA positive and BRCA negative triple negative tumors. CONCLUSION: TNBC may have a parallel orientation and posterior enhancement, which are features often seen with benign masses. BRCA mutations do not affect the imaging features of triple negative breast tumors.

Contralateral Risk-Reducing Mastectomy in Breast Cancer Patients Who Undergo Multigene Panel Testing.

BACKGROUND: An increasing number of breast cancer patients are undergoing expanded genetic testing and are being identified as germline mutation carriers. We sought to determine rates of contralateral risk-reducing mastectomy (CRRM) in patients with various germline mutations. PATIENTS AND METHODS: All women ≥ 18 years of age with unilateral breast cancer who underwent multigene panel testing between January 1, 2014 and August 1, 2019 at our academic institution were identified. Demographic, tumor, and treatment variables were identified from the medical record. Multivariable analyses were performed to compare factors associated with performance of CRRM. RESULTS: We identified 1613 patients, of whom 28.1% had a pathogenic variant and 40.1% had variants of uncertain significance (VUS). Overall, 420 patients (26.0%) underwent a CRRM. On multivariable analysis, factors associated with CRRM included age < 50 years (OR 3.8, 95% CI 3.0, 5.0), race (OR 0.5, 95% CI 0.3, 0.7 and OR 0.4, 95% CI 0.2, 0.7 for Black and Asian women, respectively, versus White women), and the presence of any germline mutation or VUS (OR 13.2, 95% CI 8.7, 20.2 for BRCA1/2; OR 3.9, 95% CI 2.7, 5.8 for non-BRCA germline mutation; and OR 1.8, 95% CI 1.3, 2.6 for VUS). CONCLUSIONS: In breast cancer patients who undergo multigene panel testing, a sizeable number of women with pathogenic non-BRCA germline findings are opting for CRRM. Given that the risk of contralateral breast cancer in women with most pathogenic mutations other than BRCA1/2 remains poorly characterized, these data have implications for risk counseling and for ascertaining the true risks of contralateral breast cancer in this population.

Biomarker Modulation Study of Celecoxib for Chemoprevention in Women at Increased Risk for Breast Cancer: A Phase II Pilot Study.

In preclinical studies, celecoxib has been associated with reduced risk of breast cancer. In this study, the aim was to assess the biomodulatory effect of celecoxib on blood and benign breast tissue biomarkers in women at increased risk for breast cancer. Women at increased risk for breast cancer [5-year Gail risk score of >1.67%, history of atypical hyperplasia, lobular carcinoma in situ, or previous estrogen receptor (ER)-negative breast cancer] were treated with celecoxib at 400 mg orally twice daily for 6 months. Participants underwent random periareolar fine needle aspiration and blood draw at baseline and at 6 months for analysis of biomarkers: serum levels of insulin-like growth factor 1 (IGF-1), IGF-binding protein 1 (IGFBP-1), and IGFBP-3; tissue expression of Ki-67 and ER; as well as cytology. Forty-nine patients were eligible for analysis. Median IGFBP-1 levels increased significantly from 6.05 ng/mL at baseline to 6.93 ng/mL at 6 months (P = 0.04), and median IGFBP-3 levels decreased significantly from 3,593 ng/mL to 3,420 ng/mL (P = 0.01). We also detected favorable changes in cytology of 52% of tested sites after 6 months of celecoxib therapy. No changes in tissue Ki-67 and ER expression levels were observed. No grade 3 or 4 toxicity was recorded. Celecoxib was well tolerated and induced favorable changes in serum biomarkers as well as cytology in this pilot phase II trial. A phase IIb placebo-controlled study with celecoxib could be considered for women at increased risk for breast cancer.

Clinical outcome and toxicity from taxanes in breast cancer patients with BRCA1 and BRCA2 pathogenic germline mutations.

Germline variations in genes coding for proteins involved in the oxidative stress and DNA repair greatly influence drug response and toxicity. Because BRCA1 and BRCA2 proteins play a role in DNA damage repair, we postulated that taxane-related toxicity is potentially higher and clinical outcome in different in patients with BRCA pathogenic variants (PV). Seven hundred nineteen women who underwent BRCA genetic testing and were treated with taxane-containing chemotherapy for early-stage breast cancer between 1997 and 2018 were included in the study. Patients with BRCA variants of uncertain significance were excluded. The Kaplan-Meier product-limit method was used to estimate recurrence-free survival (RFS) and overall survival (OS) rates. Logistic regression models were used to assess the association between chemotherapy toxicity and factors of interest. Cox regression models were used to assess the association between RFS and OS and factors of interest. Ninety-four (13%) and 54 (7%) patients had BRCA1 and BRCA2-PVs, respectively. While anemia (P = .0025) and leukopenia (P = .001) were more frequently seen in BRCA noncarriers, there was no difference in regards to peripheral neuropathy or other toxicities between the groups. Increasing doses of taxane were associated with increased risk of neutropenia, stomatitis, nausea, vomiting, acne/rash, and peripheral neuropathy across all groups. In a multivariate logistic regression model, BRCA2 status remained as an independent significant predictor for decreased hematologic toxicity (HR: 0.36; 95% CI: 0.20-0.67; P = .001) and increased gastrointestinal toxicity (HR: 1.93; 95% CI: 1.02-3.67; P = .04). Being overweight, obese and African-American race were significant predictors for peripheral neuropathy (P = .04; P = .03; P = .06, respectively). Total taxane dose received did not have any impact on survival outcomes. Our study demonstrates that taxane-containing chemotherapy regimens do not increase risk of peripheral neuropathy or hematologic toxicity in patients with BRCA PVs. The mechanisms for this finding need to be further investigated as it may provide an opportunity to combine taxanes with other agents, such as platinum salts or PARP inhibitors, with less anticipated toxicity.

Prospective Evaluation of Universal BRCA Testing for Women With Triple-Negative Breast Cancer.

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.

Multigene panel testing results in patients with multiple breast cancer primaries.

Currently, the NCCN guidelines recommend testing of BRCA1 and BRCA2 for females with multiple breast primaries, if her first diagnosis was ≤50 years old. With the increase in uptake of multigene panels, testing for genes outside of BRCA1 and BRCA2 has become more prevalent. This study looked at a single institution's cohort of women with multiple primary breast cancers that underwent panel testing to determine the rates of pathogenic mutations in non-BRCA genes. The genetic testing results for each individual were reviewed, along with patient characteristics. Descriptive analysis and two-tailed Z tests were used to analyze the data. Out of 85 eligible women, 33 (38.8%) tested positive for a pathogenic mutation in a cancer predisposition gene: 9 BRCA1, 5 BRCA2, 5 ATM, 1 BARD1, 4 CHEK2, 1 MSH2, 1 MSH6, 2 PALB2, 1 PMS2, 1 PTEN and 3 TP53. Overall, 17.6% tested positive for a non-BRCA breast cancer predisposition gene. There was no difference in the age of first or second breast cancer diagnosis in comparison with genetic testing outcomes. This study found a high positive rate for all individuals with multiple breast cancers, regardless of age, for both BRCA1 and BRCA2 and non-BRCA genes. Future studies should investigate whether individuals with multiple breast cancer primaries that do not meet BRCA1 and BRCA2 testing criteria should undergo genetic testing, regardless of the age of diagnosis.

Elevated serum levels of sialyl Lewis X (sLeX) and inflammatory mediators in patients with breast cancer.

PURPOSE: The carbohydrate sialyl LewisX (sLeX) 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 sLeX and inflammatory cytokines/chemokines in breast cancer sera. METHODS: We retrospectively measured sLeX 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 sLeX 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 sLeX using a cut-off of 8 U/mL as previously defined. RESULTS: Median serum sLeX 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 sLeX > 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). sLeX, MCP-1 and IP-10 remained significant in multivariate survival analysis. CONCLUSION: Elevated serum sLeX was associated with invasive cancer but not DCIS. High serum sLeX 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 sLeX may have prognostic value in breast cancer.

Contralateral prophylactic mastectomy rate and predictive factors among patients with breast cancer who underwent multigene panel testing for hereditary cancer.

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.