A machine learning one-class logistic regression model to predict stemness for single cell transcriptomics and spatial omics.

Cell annotation is a crucial methodological component to interpreting single cell and spatial omics data. These approaches were developed for single cell analysis but are often biased, manually curated and yet unproven in spatial omics. Here we apply a stemness model for assessing oncogenic states to single cell and spatial omic cancer datasets. This one-class logistic regression machine learning algorithm is used to extract transcriptomic features from non-transformed stem cells to identify dedifferentiated cell states in tumors. We found this method identifies single cell states in metastatic tumor cell populations without the requirement of cell annotation. This machine learning model identified stem-like cell populations not identified in single cell or spatial transcriptomic analysis using existing methods. For the first time, we demonstrate the application of a ML tool across five emerging spatial transcriptomic and proteomic technologies to identify oncogenic stem-like cell types in the tumor microenvironment.

Association of RAD51C germline mutations with breast cancer among Bahamians.

PURPOSE: RAD51C is known as an ovarian cancer gene; however, its role in breast cancer susceptibility is less clear. As part of a larger study, we assessed the role of germline RAD51C mutations in breast cancer development. METHODS: We studied 387 unselected, BRCA1- and BRCA2-negative, Bahamian breast cancer cases and 653 controls to search for novel genetic associations with breast cancer development. During the first phase of the study, whole exome sequencing was utilized in 96 cases to identify an association between novel genes and breast cancer susceptibility. In the second phase of the study, targeted gene sequencing was utilized in the entirety of the cases and controls to identify an association between novel genetic mutations and breast cancer development. RESULTS: A RAD51C mutation was found in five breast cancer cases and in no control (5/387 versus 0/653; p = 0.007). None of the mutation-positive cases reported a family history of ovarian cancer. CONCLUSIONS: These data support increasing evidence that RAD51C mutations contribute to breast cancer susceptibility, although the impact may vary substantially from country to country.

Immune Checkpoint Inhibitors and the Risk of Allograft Rejection: A Comprehensive Analysis on an Emerging Issue.

BACKGROUND: It is well known that the state of immune tolerance induced by broad immunosuppression to prevent allograft rejection leads to an increased risk of the development of cancer. One of the most promising new areas of cancer treatment has been the development of immune checkpoint inhibitors that target the cytotoxic T-lymphocyte-associated antigen 4 and programmed cell death protein 1/programmed death-ligand 1 (PD-L1) pathways. As a logical consequence, growing interest in these agents translated into their implementation in patients with transplant-related malignancies. Because of overlapping and perhaps mutually exclusive mechanisms of action of transplant immunosuppression and cancer immunomodulation, it is critical to examine these interactions. MATERIALS AND METHODS: We carried out a systematic search for review articles and case reports published between July 2014 and November 2017 using three engines: Usearch, PubMed, and Up-to-date. RESULTS: Overall, there were 20 cases with 12 allograft rejections. The rejection rate associated with nivolumab was 73% (8/11) and with pembrolizumab it was 100% (2/2). The use of ipilimumab did not lead to rejection in any instance (0/4, 0%). Of the two patients treated with the sequential use of ipilimumab/nivolumab, one lost his allograft, yielding a rejection rate of 50%. The sequential use of ipilimumab/pembrolizumab led to a rejection rate of 100% (1/1, 100%). CONCLUSION: The use of agents that act on the PD-L1 pathway are contraindicated in the face of solid organ allografts because of unacceptably high rates of irreversible allograft rejection. It appears that the use of ipilimumab may be tolerated as the mechanism is different from that of the PD-L1 agents. IMPLICATIONS FOR PRACTICE: Transplant rejection is a complex process that puts stress on patients and their families and can lead to tragic results. Significant advancements in the field of immunosuppression have led to the engenderment of agents devised to extend the survival of transplant recipients. The advent of immunomodulators in cancer therapy has been paradigm-shifting; however, because of their mechanism of action, their use must be carefully considered in patients with allografts and concomitant cancer. It appears that ipilimumab can be administered safely in these patients but that agents acting on the programmed death-ligand 1 pathway are contraindicated because of high rates of irreversible rejection.

Differences in breast cancer outcomes amongst Black US-born and Caribbean-born immigrants.

BACKGROUND: There are few studies that directly investigate disparities in outcome within the African diaspora in the US. We investigated the association between nativity of Black women diagnosed with breast cancer (Caribbean or USA place of birth) and ethnicity, age at diagnosis, treatment, tumor characteristics and outcome. METHODS: The data were obtained from the University of Miami Health System, and Jackson Health System. Individual-level data from 1132 cases was used to estimate hazard rations (HRs) of women born in the Caribbean (Caribbean Blacks, CB) or in the USA (US Black, USB) using Cox proportional hazards regression analysis for overall survival. RESULTS: The cohort contains data from 624 (54.9%) USB women and 507 (45%) CB women diagnosed with breast cancer between 2006 and 2017. Compared to CB patients, USB patients had more Estrogen Receptor negative (31.4% vs. 39.1%, P = 0.018) and triple negative breast cancers (19.6% vs. 27.9%, P = 0.003). CB women presented at more advanced stages III/IV (44.2% vs. 35.2%; P = 0.016). CB patients showed a better overall survival (hazard ratio, HR = 0.75; 95% CI 0.59-0.96; P = 0.024). Overall Black Hispanic patients had a better overall survival (HR = 0.51; 95% CI 0.28-0.93; P = 0.028) compared to non-Hispanic Black patients. CONCLUSION: In conclusion the study found that CB immigrants diagnosed with breast cancer have an improved overall survival when compared with USB patients. This finding suggests that within the African diaspora in the USA, additional factors beyond race contribute to worse outcomes in African Americans.

A clinically structured and partnered approach to genetic testing in Trinidadian women with breast cancer and their families.

INTRODUCTION: Breast cancer (BC) is the leading cause of cancer death in Caribbean women. Across the Caribbean islands, the prevalence of hereditary breast cancer among unselected breast cancer patients ranges from 5 to 25%. Moreover, the prevalence of BC among younger women and the high mortality in the Caribbean region are notable. This BC burden presents an opportunity for cancer prevention and control that begins with genetic testing among high-risk women. Measured response to positive genetic test results includes the number of preventive procedures and cascade testing in family members. We previously reported data on an active approach to promote cascade testing in the Bahamas and report on preventive procedures showing moderate uptake. Here, we describe a clinically structured and community-partnered approach to the dissemination and follow-up of genetic test results including family counseling for the promotion of risk mitigation strategies and cascade testing in our Trinidadian cohort of patients tested positive for BC predisposition genes. METHODS: As a part of our initial study of BC genetic testing in Trinidad and Tobago, all participants received pre-test counseling including three-generation pedigree and genetic testing for BRCA1/2, PALB2, and RAD51C. The study was approved by the University of Miami IRB and the Ethics Committee of the Ministry of Health, Trinidad and Tobago. We prospectively evaluated a clinically structured approach to genetic counseling and follow-up of BC mutation carriers in Trinidad and Tobago in 2015. The intervention consisted of (1) engaging twenty-nine BC patients with a deleterious gene mutation (probands), and (2) invitation of their at-risk relatives to attend to a family counseling session. The session included information on the meaning of their results, risk of inheritance, risk of cancer, risk-reduction options, offering of cascade testing to family members, and follow-up of proband decision-making over two years. RESULTS: Twenty-four of twenty-nine mutation carriers (82.8%) consented to enroll in the study. At initial pedigree review, we identified 125 at-risk relatives (ARR). Seventy-seven ARR (62%) attended the family counseling sessions; of these, 76 ARR (99%) consented to be tested for their family gene mutation. Genetic sequencing revealed that of the 76 tested, 35 (46%) ARR were carriers of their family mutation. The ARR received their results and were urged to take preventative measures at post-test counseling. At 2-year follow-up, 6 of 21 probands with intact breasts elected to pursue preventive mastectomy (28.5%) and 4 of 20 women with intact ovaries underwent RRSO (20%). CONCLUSIONS: In Trinidad and Tobago, a clinically structured and partnered approach to our testing program led to a significant rate of proband response by completing the intervention counseling session, executing risk-reducing procedures as well as informing and motivating at-risk relatives, thereby demonstrating the utility and efficacy of this BC control program.

Endometrial cancer outcomes among non-Hispanic US born and Caribbean born black women.

PURPOSE: Data on endometrial cancer outcomes among immigrant women in the USA are lacking. The objective was to determine the effect of Caribbean nativity on outcomes in black women with endometrial cancer compared with women born in the USA, with attention paid to the effects of tumor grade, sociodemographic factors, and treatment approaches. METHODS: A review of the institutional cancer registry was performed to identify black, non-Hispanic women with known nativity and treated for endometrial cancer between 2001 and 2017. Sociodemographic, treatment, and outcomes data were collected. Analyses were done using the χ2 test, Cox proportional hazards models, and the Kaplan-Meier method, with significance set at P<0.05. RESULTS: 195 women were included in the analysis. High grade histologies were present in a large proportion of both US born (64.5%) and Caribbean born (72.2%) patients. Compared with US born women, those of Caribbean nativity were more likely to be non-smokers (P=0.01) and be uninsured (P=0.03). Caribbean born women had more cases of stage III disease (27.8% versus 12.5%, P<0.01), while carcinosarcoma was more common in US born black women (23.6% versus 10.6%, P=0.05). Caribbean nativity trended towards improvement in overall survival (hazard ratio (HR) 0.65 (0.40-1.07)). Radiation (HR 0.53 (0.29-1.00)) was associated with improved survival while advanced stage (HR 3.81 (2.20-6.57)) and high grade histology (HR 2.34 (1.17-4.72)) were predictive of worse survival. CONCLUSIONS: The prevalence of high grade endometrial cancer histologies among black women of Caribbean nativity is higher than previously reported. Caribbean nativity may be associated with improved overall survival although additional study is warranted.

A high frequency of PALB2 mutations in Jamaican patients with breast cancer.

PURPOSE: Jamaica is an island nation with one of the highest breast cancer incidence rates in the Caribbean (40/100,000 per year). The contribution of cancer susceptibility gene mutations to the burden of breast cancer in Jamaica has not yet been explored. We sought to determine the prevalence of germline mutations in BRCA1, BRCA2, and PALB2 in 179 unselected Jamaican women with breast cancer. METHODS: We sequenced the entire coding regions of BRCA1, BRCA2, and PALB2 for all the study subjects. RESULTS: Overall, 8 of 179 patients (4.5%) had a mutation in one of the three genes: one in BRCA1, two in BRCA2, and five in PALB2. CONCLUSIONS: These data suggest that in addition to BRCA1 and BRCA2, PALB2 should be included in genetic testing for breast cancer patients in Jamaica.

A Survey of BRCA1, BRCA2, and PALB2 mutations in women with breast cancer in Trinidad and Tobago.

The mortality rate from breast cancer in the nation of Trinidad and Tobago is among the highest of any country in the Caribbean region. The contribution of inherited gene mutations to the burden of breast cancer in Trinidad and Tobago has not been studied. We examined the prevalence of mutations in three susceptibility genes (BRCA1, BRCA2, and PALB2) in breast cancer patients in Trinidad and Tobago. We studied 268 unselected breast cancer patients from Trinidad and Tobago and looked for mutations across the entire coding sequences of BRCA1, BRCA2, and PALB2. Overall, 28 of 268 patients (10.4 %) had a mutation in one of the three genes, including 15 in BRCA1, ten in BRCA2, two in PALB2, and one in both BRCA2 and PALB2. There were 25 different mutations identified; of these, four mutations were seen in two patients each. Given the high prevalence of mutations, it is reasonable to offer genetic testing for these three genes to all breast cancer patients in Trinidad and Tobago.

Clinical outcomes in breast cancer patients with HIV/AIDS: a retrospective study.

The purpose of the study is to describe what is the presentation of breast cancer in women with HIV, their tolerance to therapy, the most common complications of treatment and their outcomes. Retrospective chart review of patients with HIV diagnosed with breast cancer between January 1, 1989 and December 31, 2013 at the University of Miami/Jackson Memorial Hospital (UM/JMH) 47 females and 1 male were included in the analysis. The median age of diagnosis was 46 years (IQR 41-52) and 64% of the women were premenopausal. Median CD4(+) count was 330 cells/µL (IQR 131-589 cells/µL). 41% had AIDS at time of diagnosis. 94% of patients presented with locoregional disease and 6% with late stage breast cancer. 52% had ER(+) tumors. 6% had HER-2/neu tumor expression and 21 % had triple negative disease. The 5 year PFS was 50% (95% CI 34-64%), the 5 year OS was 44% (95% CI 29-58%), and the Breast cancer-specific survival was 57% (95% CI 40-70%). Death was attributed to breast cancer in 22 patients, AIDS progression in 6 patients, other medical condition in 1, and for 4, the cause was unknown. Serious adverse events were documented in 46% of patients treated with chemotherapy. Targeted therapy was well tolerated. Patients with HIV/AIDS and breast cancer pose a major challenge for oncologists. Surgery, radiation, and endocrine therapy are well tolerated. Standard dose chemotherapy can have life-threatening side effects which can be managed with growth factor support and antimicrobial prophylaxis. All cancer therapy can be given while continuing with antiviral therapy at full dose.

How do we choose?

The Hearts and Minds of Ghana project improves the lives of those who are less fortunate and have few resources. Providing clear goals for the mission, devising prior guidelines for patient selection and treatment, achieving a better understanding of local culture and expectations, and good team work, facilitate making better ethical decisions, but doesn't make them less difficult.

The Genetic Paradigm of Hereditary Breast and Ovarian Cancer (HBOC) in the Afro-Caribbean Population.

Differences in tumor biology and genetic predisposition have been suggested as factors influencing overall survival and increased mortality in Black breast and ovarian cancer patients. Therefore, it is key to evaluate genetic susceptibilities in Afro-Caribbean patients because the black population in the US is not homogeneous. Identifying a high incidence of hereditary breast and ovarian cancer (HBOC) in Afro-Caribbean countries can lead to understanding the pattern of inherited traits in US-Caribbean immigrants and their subsequent generations. The paucity of projects studying the genetic landscape in these populations makes it difficult to design studies aimed at optimizing screening and prophylaxis strategies, which in turn, improve survival and mortality rates. This scoping review identifies and categorizes current research on the genetic paradigm of HBOC in the Afro-Caribbean population. We performed an evaluation of the evidence and generated a summary of findings according to preferred reporting items for systematic review and meta-analysis (PRISMA) Extension for Scoping Reviews guidelines. We included articles that assessed the incidence and prevalence of pathologic germline mutations and experience/barriers for genetic testing in Afro-Caribbean Countries and US-Caribbean patients. Our results highlight countries where genetic landscapes remain severely understudied and support recommending multigene testing in Caribbean-born patients. They highlight a need for further research on the genetic paradigm of HBOC in the Afro-Caribbean population to improve genetic testing/counseling and the subsequent adoption of early detection and risk reduction strategies.

Predictors of locoregional outcome in patients receiving neoadjuvant therapy and postmastectomy radiation.

BACKGROUND: The objective of this study was to identify predictors of locoregional recurrence (LRR) after neoadjuvant therapy (NAT) and postmastectomy radiation (PMRT) in a cohort of patients with stage II through III breast cancer and to determine whether omission of the supraclavicular field had an impact on the risk of LRR. METHODS: The authors reviewed records from 464 patients who received NAT and PMRT from January 1999 to December 2009. RESULTS: The median patient age was 50 years (range, 25-81 years). Clinical disease stage was stage II in 29% of patients, stage III in 71%, and inflammatory in 14%. Receptor status was estrogen receptor (ER)-positive in 54% of patients, progesterone receptor (PR)-positive in 39%, human epidermal growth factor receptor 2 (HER2)-positive in 24%, and negative for all 3 receptors (triple negative) in 32%. All patients received NAT and underwent mastectomy, and 19.6% had a complete pathologic response in the breast and axilla, 17.5% received radiation to the chest wall only, and 82.5% received radiation to the chest wall and the supraclavicular field; omission of the supraclavicular field was more common in patients with lower clinical and pathologic lymph node status. The median follow-up was 50.5 months, and the 5-year cumulative incidence of LRR was 6% (95% confidence interval, 3.9%-8.6%). Predictors of LRR were clinical stage III (P = .038), higher clinical lymph node status (P = .025), higher pathologic lymph node status (P = .003), the combination of clinically and pathologically positive lymph nodes (P < .001), inflammatory presentation (P = .037), negative ER status (P = .006), negative PR status (P = .015), triple-negative status (P < .001), and pathologic tumor size >2 cm (P = .045). On univariate analysis, omission of the supraclavicular field was not associated significantly with LRR (hazard ratio, 0.89; P = .833); however, on multivariate analyses, omission of the supraclavicular field was associated significantly with LRR (hazard ratio, 3.39; P = .024). CONCLUSIONS: Presenting stage, receptor status, pathologic response to neoadjuvant therapy, and omission the supraclavicular field were identified as risk factors for LRR after neoadjuvant therapy and PMRT.

The use of neoadjuvant platinum-based chemotherapy in locally advanced breast cancer that is triple negative: retrospective analysis of 144 patients.

Triple-negative breast cancers comprise about 20 % of breast cancers. They have poor prognosis and have no standard therapy. The aim of this study was to evaluate pathologic complete response (pCR), progression-free survival (PFS), and overall survival (OS) in patients with TNBC treated with neoadjuvant platinum-based chemotherapy. This is a retrospective study of one hundred and forty-four women with TNBC treated with neoadjuvant platinum-containing chemotherapy for locally advanced breast cancer at the University of Miami between January 1, 1999, and January 1, 2011. The medical record was reviewed to obtain data on clinical characteristics, including ethnicity, race, age, clinical stage, treatment regimen, and vital status. This study was approved by the University of Miami IRB. All patients had locally advanced breast cancer with at least one of the following features at presentation: T3, T4, N2, and N3. The mean tumor size by palpation was 9.4 cm. The clinical T-stage at presentation was 1.4 % T1, 8.3 % T2, 52.8 % T3, and 37.5 % T4 (19.4 % T4d). The nodal status by physical exam at presentation was 23 % N0, 37.5 % N1, 34 % N2, and 5.5 % N3. pCR in breast and axilla was seen in 31 %. PFS and OS were 55 and 59 %, respectively, at 7 years. Cisplatin offered a survival advantage over carboplatin in both PFS (P = 0.007) and OS (P = 0.018). Node positivity was the most important predictor of survival. Cisplatin/docetaxel neoadjuvant therapy was well tolerated and an effective therapy in locally advanced TNB.

Impact of surgery-radiation interval on locoregional outcome in patients receiving neo-adjuvant therapy and mastectomy.

Delays in the initiation of radiation are increasingly common for medically underserved patients. We evaluated the impact of delay in initiation of postmastectomy radiation (PMRT) in breast cancer patients treated with neo-adjuvant therapy (NAT) in a cohort of medically underserved patients with multiple barriers to timely care. We retrospectively reviewed medical records of 248 consecutively treated patients. Clinical stage was 34.4% II, 65.6% III. The median interval from surgery to PMRT was 11.9 weeks; 22.2% started PMRT within 8 weeks of surgery, 52% within 12 weeks, and 67.3% within 16 weeks. The cumulative 5-year incidence of locoregional recurrence (LRR) was 5.8% (95% CI: 3.2-9.7). There was no significant difference in locoregional outcome among patients starting PMRT within 8 weeks versus >8 weeks (p = 0.634), ≤ 12 versus >12 weeks (p = 0.332), or ≤ 16 versus >16 weeks (p = 0.549) after surgery. Although timely initiation of PMRT remains a priority, the locoregional control benefit of PMRT appears to be maintained up to at least 16 weeks, and in those without early locoregional recurrence, PMRT should be offered despite such a delay.

Time to Cancer Treatment and Chemotherapy Relative Dose Intensity for Patients With Breast Cancer Living With HIV.

Importance: Patients with breast cancer and comorbid HIV experience higher mortality than other patients with breast cancer. Objective: To compare time to cancer treatment initiation and relative dose intensity (RDI) of neoadjuvant and adjuvant chemotherapy among patients with breast cancer with vs without HIV. Design, Setting, and Participants: A retrospective, matched cohort study enrolled women who received a diagnosis of breast cancer from January 1, 2000, through December 31, 2018. The electronic medical records of 3 urban, academic cancer centers were searched for women with confirmed HIV infection prior to or simultaneous with diagnosis of stage I to III breast cancer. Tumor registry data were used to identify 2 control patients with breast cancer without HIV for each participant with HIV, matching for study site, stage, and year of cancer diagnosis. Statistical analysis was performed from December 2022 to October 2023. Exposure: HIV infection detected before or within 90 days of participants' breast cancer diagnosis. Main Outcomes and Measures: The primary outcome was time to breast cancer treatment initiation, defined as the number of days between cancer diagnosis and first treatment. The secondary outcome was overall RDI for patients who received chemotherapy. These outcomes were compared by HIV status using Cox proportional hazards regression and linear regression modeling, respectively, adjusting for confounding demographic and clinical factors. Exploratory outcomes included instances of anemia, neutropenia, thrombocytopenia, and liver function test result abnormalities during chemotherapy, which were compared using Fisher exact tests. Results: The study enrolled 66 women with comorbid breast cancer and HIV (median age, 51.1 years [IQR, 45.7-58.2 years]) and 132 with breast cancer alone (median age, 53.9 years [IQR, 47.0-62.5 years]). The median time to first cancer treatment was not significantly higher among patients with HIV than those without (48.5 days [IQR, 32.0-67.0 days] vs 42.5 days [IQR, 25.0-59.0 days]; adjusted hazard ratio, 0.78, 95% CI, 0.55-1.12). Among the 36 women with HIV and 62 women without HIV who received chemotherapy, the median overall RDI was lower for those with HIV vs without HIV (0.87 [IQR, 0.74-0.97] vs 0.96 [IQR, 0.88-1.00]; adjusted P = .01). Grade 3 or higher neutropenia during chemotherapy occurred among more women with HIV than those without HIV (13 of 36 [36.1%] vs 5 of 58 [8.6%]). Conclusions and Relevance: This matched cohort study suggests that patients with breast cancer and HIV may have experienced reduced adjuvant chemotherapy RDI, reflecting greater dose reductions, delays, or discontinuation. Strategies for supporting this vulnerable population during chemotherapy treatment are necessary.

A high prevalence of BRCA1 mutations among breast cancer patients from the Bahamas.

The Bahamas is a group of islands in the Caribbean with a high incidence of early onset breast cancer. In isolated populations, the identification of founder mutations in cancer predisposing genes may facilitate genetic testing and counseling. To date, six distinct BRCA1 mutations have been found in patients from cancer families from the Bahamas. The frequencies of these mutant alleles have not been measured in a large series of unselected breast cancer patients from Bahamas. We studied 214 Bahamian women with invasive breast cancer, unselected for age or family history of cancer. All patients were screened for six mutations in the BRCA1 gene that have previously been reported in cancer patients from the Bahamas. A mutation was identified in 49 of the 214 breast cancer patients (23%). The mutation frequency was particularly high in women diagnosed before age 50 (33%) in women with a first-degree relative with breast or ovarian cancer (41%) and in women with bilateral breast cancer (58%). Approximately 23% of unselected cases of breast cancer in the Bahamian population are attributable to a founder mutation in the BRCA1 gene-this is the highest reported mutation prevalence for any country studied to date. Genetic testing for these mutations is advisable for all women diagnosed with breast cancer in the Bahamas.

Gene Sequencing for Pathogenic Variants Among Adults With Breast and Ovarian Cancer in the Caribbean.

Importance: Rates of breast and ovarian cancer are high in the Caribbean; however, to date, few published data quantify the prevalence of inherited cancer in the Caribbean population. Objective: To determine whether deleterious variants in genes that characterize the hereditary breast and ovarian cancer syndrome are associated with the development of breast and ovarian cancer in the English- and Creole-speaking Caribbean populations. Design, Setting, and Participants: This multisite genetic association study used data from germline genetic test results between June 2010 and June 2018 in the Bahamas, Cayman Islands, Barbados, Dominica, Jamaica, Haiti, and Trinidad and Tobago. Next-generation sequencing on a panel of 30 genes and multiplex ligation-dependent probe amplification (BRCA1 and BRCA2) were performed. Medical records were reviewed at time of study enrollment. Women and men diagnosed with breast and ovarian cancer with at least 1 grandparent born in the participating study sites were included; 1018 individuals were eligible and consented to participate in this study. Data were analyzed from November 4, 2019, to May 6, 2020. Exposures: Breast and/or ovarian cancer diagnosis. Main Outcomes and Measures: Rate of inherited breast and ovarian cancer syndrome and spectrum and types of variants. Results: Of 1018 participants, 999 (98.1%) had breast cancer (mean [SD] age, 46.6 [10.8] years) and 21 (2.1%) had ovarian cancer (mean [SD] age, 47.6 [13.5] years). Three individuals declined to have their results reported. A total of 144 of 1015 (14.2%) had a pathogenic or likely pathogenic (P/LP) variant in a hereditary breast and ovarian cancer syndrome gene. A total of 64% of variant carriers had P/LP variant in BRCA1, 23% in BRCA2, 9% in PALB2 and 4% in RAD51C, CHEK2, ATM, STK11 and NBN. The mean (SD) age of variant carriers was 40.7 (9.2) compared with 47.5 (10.7) years in noncarriers. Individuals in the Bahamas had the highest proportion of hereditary breast and ovarian cancer (23%), followed by Barbados (17.9%), Trinidad (12%), Dominica (8.8%), Haiti (6.7%), Cayman Islands (6.3%), and Jamaica (4.9%). In Caribbean-born women and men with breast cancer, having a first- or second-degree family member with breast cancer was associated with having any BRCA1 or BRCA2 germline variant (odds ratio, 1.58; 95% CI, 1.24-2.01; P < .001). A BRCA1 vs BRCA2 variant was more strongly associated with triple negative breast cancer (odds ratio, 6.33; 95% CI, 2.05-19.54; P = .001). Conclusions and Relevance: In this study, among Caribbean-born individuals with breast and ovarian cancer, 1 in 7 had hereditary breast and ovarian cancer. The proportion of hereditary breast and ovarian cancer varied by island and ranged from 23% in the Bahamas to 4.9% in Jamaica. Each island had a distinctive set of variants.

Final results of a phase II study of nab-paclitaxel, bevacizumab, and gemcitabine as first-line therapy for patients with HER2-negative metastatic breast cancer.

In order to examine the efficacy and safety of nanoparticle albumin-bound paclitaxel (nab-P) in combination with bevacizumab (B) and gemcitabine (G) for the first-line treatment of patients with HER2-negative metastatic breast cancer (MBC). In this single-center, open-label phase II trial, patients with HER2-negative MBC received gemcitabine 1500 mg/m(2), nab-paclitaxel 150 mg/m(2), and bevacizumab 10 mg/kg (each administered intravenously) on days 1 and 15 of a 28-day cycle. The primary end point was progression free survival (PFS); secondary end points were overall response rate (ORR), complete (CR) and partial (PR) response rates, clinical benefit (ORR + stable disease), overall survival (OS), and safety. Thirty patients were enrolled. One patient was ineligible and was not included in analysis. Median PFS was 10.4 months (95% CI: 5.6-15.2 months). ORR was 75.9%, comprising eight (27.6%) CRs and 14 (48.3%) PRs; five patients had stable disease (SD) and two patients (6.9%) had progressive disease (PD) as their best response. The clinical benefit rate was 93.1% (27/29) in the overall group and 84.6% in the triple-negative cohort (11/13). The 18-month survival rate was 77.2% (95% CI: 51.1-90.5%). Eight (27.6%) patients experienced grade 3 or 4 toxicity: grade 4 neutropenic fever (n = 1) and grade 3 infection (n = 6), leukopenia, thrombocytopenia, peripheral neuropathy, seizure, shortness of breath, hematuria, and cardiac tamponade (one each). First-line therapy with nab-P, B, and G demonstrated a median PFS of 10.4 months and a 75.9% ORR with acceptable toxicity; this novel combination warrants investigation in a randomized study.

The role of combination inhaled corticosteroid/long-acting beta-agonist therapy in COPD management.

Chronic obstructive pulmonary disease (COPD) is now the fourth leading cause of death, affects an estimated 24 million Americans, and accounts for over ten million physician and emergency department (ED) visits and hospitalisations each year. The diagnosis and management of COPD falls largely to primary care practitioners. Previously, COPD management options were limited, but newer treatments have been shown to slow lung deterioration, reduce symptoms and preserve quality of life. Combination therapy with an inhaled corticosteroid and a long-acting beta2-agonist (ICS/LABA) is an effective therapy for COPD that, compared to other therapies, has been shown to reduce exacerbations, hospitalisations, ED visits and health care costs. This review focuses on the role of combination ICS/LABA therapy in managing COPD, including indications, potential benefits and considerations that affect therapy decisions.

Cancer Risks Associated With Germline PALB2 Pathogenic Variants: An International Study of 524 Families.

PURPOSE: To estimate age-specific relative and absolute cancer risks of breast cancer and to estimate risks of ovarian, pancreatic, male breast, prostate, and colorectal cancers associated with germline PALB2 pathogenic variants (PVs) because these risks have not been extensively characterized. METHODS: We analyzed data from 524 families with PALB2 PVs from 21 countries. Complex segregation analysis was used to estimate relative risks (RRs; relative to country-specific population incidences) and absolute risks of cancers. The models allowed for residual familial aggregation of breast and ovarian cancer and were adjusted for the family-specific ascertainment schemes. RESULTS: We found associations between PALB2 PVs and risk of female breast cancer (RR, 7.18; 95% CI, 5.82 to 8.85; P = 6.5 × 10-76), ovarian cancer (RR, 2.91; 95% CI, 1.40 to 6.04; P = 4.1 × 10-3), pancreatic cancer (RR, 2.37; 95% CI, 1.24 to 4.50; P = 8.7 × 10-3), and male breast cancer (RR, 7.34; 95% CI, 1.28 to 42.18; P = 2.6 × 10-2). There was no evidence for increased risks of prostate or colorectal cancer. The breast cancer RRs declined with age (P for trend = 2.0 × 10-3). After adjusting for family ascertainment, breast cancer risk estimates on the basis of multiple case families were similar to the estimates from families ascertained through population-based studies (P for difference = .41). On the basis of the combined data, the estimated risks to age 80 years were 53% (95% CI, 44% to 63%) for female breast cancer, 5% (95% CI, 2% to 10%) for ovarian cancer, 2%-3% (95% CI females, 1% to 4%; 95% CI males, 2% to 5%) for pancreatic cancer, and 1% (95% CI, 0.2% to 5%) for male breast cancer. CONCLUSION: These results confirm PALB2 as a major breast cancer susceptibility gene and establish substantial associations between germline PALB2 PVs and ovarian, pancreatic, and male breast cancers. These findings will facilitate incorporation of PALB2 into risk prediction models and optimize the clinical cancer risk management of PALB2 PV carriers.