Left ventricular global longitudinal strain is worse in BRCA mutation positive breast cancer patients prior to cancer treatment and premature menopause.

PURPOSE: Breast cancer patients with mutations in human tumor suppressor genes BRCA1 and BRCA2 are at higher risk of cardiovascular disease (CVD) than the general population, as they are frequently exposed to cardiotoxic chemotherapy, anti-estrogen therapy, radiation, and/or oophorectomy for cancer-related treatment and prophylaxis. Animal and cell culture models suggest that BRCA mutations may play an independent role in heart failure. We sought to evaluate cardiac structure and function in female BRCA1 and BRCA2 mutation carriers with breast cancer compared to BRCA wildtype women with breast cancer. METHODS: We performed a 1:2 age- and hypertension-matched retrospective cohort study comparing BRCA1 and BRCA2 mutation carriers (n = 38) versus BRCA wildtype controls (n = 76) with a new diagnosis of breast cancer. Echocardiographic data were obtained within 6 months of breast cancer diagnosis and prior to chemotherapy, anti-estrogen therapy, radiation, or oophorectomy. Left ventricular global longitudinal strain (LV-GLS), a highly sensitive marker of LV function, was measured using QLab 15 (Philips Healthcare). RESULTS: In the total cohort of 114 patients with a new diagnosis of breast cancer, the median age was 45 ± 11 years and the prevalence of hypertension was 8%. There were no differences in traditional cardiovascular disease risk factors between cases and controls. BRCA carriers had lower LV-GLS (- 18.1% ± 4.7% vs. - 20.1% ± 3.8%, p = 0.02) and greater right atrial area (12.9 cm2 ± 2.7 cm2 vs. 11.8 cm2 ± 2.0 cm2, p = 0.04) compared to controls; however, both LV-GLS and right atrial area were within the normal range. Compared to controls, BRCA carriers had a trend toward worse LV posterior wall thickness (0.89 cm ± 0.15 cm vs. 0.83 cm ± 0.16 cm, p = 0.06) although not statistically significant. CONCLUSION: In women with newly diagnosed breast cancer and prior to treatment, LV-GLS was worse in BRCA1 and BRCA2 mutation carriers compared to those with BRCA wildtype. These findings suggest that BRCA mutations may be associated with subtle changes in cardiac function. Whether differences in GLS translate to increased cardiovascular risk in women with BRCA mutations needs to be further characterized.

Impact of neoadjuvant pembrolizumab adherence on pathologic complete response in triple-negative breast cancer: a real-world analysis.

BACKGROUND: The addition of pembrolizumab (pembro) to neoadjuvant chemotherapy (NAC) is standard of care for the treatment of early triple-negative breast cancer (TNBC) after KEYNOTE-522 trial demonstrated improved pathologic complete response (pCR) rates with the combination. However, the optimal treatment strategy for TNBC remains uncertain as questions persist about which patients benefit from pembro and the best treatment schedule and regimen. We identified real-world clinical characteristics and treatment variables associated with response to NAC plus pembro. METHODS: Patients with early TNBC treated with NAC plus pembro between February 2020 and September 2023 were identified. Univariate and multivariate analysis was performed using logistic regression to identify factors associated with pCR. Cox proportional hazard prediction models were used to identify predictors of invasive disease-free survival and overall survival in this cohort. RESULTS: A pCR was achieved in 75 (63.6%) of 118 patients. Age at diagnosis (P = .04), Ki-67 (P = .004), duration from start of pembro to surgery (P = .006) and NAC to surgery (P = .01), number of cycles of pembro (P = .04) and NAC (P = .02), and completion of at least 8 cycles of pembro (P = .015) and NAC (P = .015) were each significantly associated with pCR in univariate analysis. In multivariate analysis, patients younger than 55 years at time of diagnosis (vs age > 55 years) and those completing at least 8 cycles of pembro remained predictive of pCR (OR's 2.50, 2.49, P = .035 and .037, respectively). CONCLUSIONS: In this real-world analysis of patients with TNBC treated with NAC plus pembro, younger age and the completion of at least 8 cycles of pembrolizumab were associated with pCR.

The Challenges of Treating Patients with Breast Cancer and Obesity.

Obesity is defined as a body mass index (BMI) of 30 kg/m2 or more and is associated with worse outcomes in patients with breast cancer, resulting in an increased incidence of breast cancer, recurrence, and death. The incidence of obesity is increasing, with almost half of all individuals in the United States classified as obese. Patients with obesity present with unique pharmacokinetics and physiology and are at increased risk of developing diabetes mellitus and cardiovascular disease, which leads to specific challenges when treating these patients. The aim of this review is to summarize the impact of obesity on the efficacy and toxicity of systemic therapies used for breast cancer patients, describe the molecular mechanisms through which obesity can affect systemic therapies, outline the existing American Society of Clinical Oncology (ASCO) guidelines for treating patients with cancer and obesity, and highlight additional clinical considerations for treating patients with obesity and breast cancer. We conclude that further research on the biological mechanisms underlying the obesity-breast cancer link may offer new treatment strategies, and clinicals trials that focus on the treatment and outcomes of patients with obesity and all stages of breast cancer are needed to inform future treatment guidelines.

Incidence and prognostic impact of HER2-positivity loss after dual HER2-directed neoadjuvant therapy for HER2+ breast cancer.

BACKGROUND: Loss of HER2 "positivity" can occur in patients with residual disease after neoadjuvant treatment, but the incidence of HER2-positivity loss after neoadjuvant dual HER2-targeted treatment plus chemotherapy, the current standard-of-care for most early stage HER2-positive breast cancers, is not well described. Previous studies that report the HER2 discordance rate after neoadjuvant treatment also do not include the novel HER2-low category. In this retrospective study, we determine the incidence and prognostic impact of HER2-positivity loss, including the evolution to HER2-low disease, after neoadjuvant dual HER2-targeted therapy with chemotherapy. METHODS: Clinicopathologic data for patients with stage I-III HER2+ breast cancer diagnosed between 2015 and 2019 were reviewed in this single institution retrospective study. Patients who received dual HER2-targeted treatment with chemotherapy were included, and HER2 status before and after neoadjuvant therapy was interrogated. RESULTS: A total of 163 female patients were included in the analysis with a median age of 50 years. A pathologic complete response (pCR as defined by ypT0/is) was achieved in 102 (62.5%) of 163 evaluable patients. Among the 61 patients with residual disease after neoadjuvant therapy, 36 (59.0%) had HER2-positive and 25 (41.0%) had HER2-negative residual disease. Of the 25 patients with HER2-negative residual disease, 22 (88%) of patients were classified as HER2-low. After a median follow-up of 3.3 years, patients who retained HER2-positivity after neoadjuvant treatment had a 3-year IDFS rate of 91% (95% CI, 91%-100%), while patients who lost HER2-positivity had a 3-year IDFS rate of 82% (95% CI, 67%-100%). CONCLUSION: Almost half of patients with residual disease following neoadjuvant dual HER2-targeted therapy plus chemotherapy lost HER2-positivity. The loss of HER2-positivity may not confer negative prognostic impact, although the results were limited by short follow-up time. Further research on the HER2 status after neoadjuvant treatment may help guide treatment decisions in the adjuvant setting.

A Comparison of Clinicopathologic Outcomes Across Neoadjuvant and Adjuvant Treatment Modalities in Resectable Gastric Cancer.

Importance: Treatment of resectable gastric cancer (RGC) uses a multimodal approach, including surgical treatment and chemotherapy with or without radiation therapy, and the optimal treatment strategy and timing of each of these modalities is unknown. Objective: To investigate the association of various neoadjuvant and adjuvant treatment modalities with pathologic complete response (pCR), surgical margin status (SMS), and overall survival (OS) in RGC. Design, Setting, and Participants: For this comparative effectiveness study, the National Cancer Database was interrogated to identify patients with RGC diagnosed from 2004 to 2015. Patients with gastric adenocarcinoma that was cT2-T4b, any N, and M0 and who underwent definitive surgical treatment were included. Main Outcomes and Measures: The association of 9 treatment groups (ie, neoadjuvant chemoradiation only [nCRT], neoadjuvant chemotherapy only, adjuvant chemotherapy only [aCT], adjuvant chemoradiation only [aCRT], neoadjuvant chemotherapy and adjuvant radiation, chemotherapy with timing unknown [CTTU], chemoradiation therapy with timing unknown, radiation therapy with timing unknown (RTTU), and no perioperative therapy [NT]) with 3 end points (ie, pCR, SMS, and OS) was analyzed. The analysis was done using logistic regression and Cox proportional hazards models with adjustment for baseline characteristics. Data were analyzed from September 2019 through February 2020. Results: Among 183 204 patients with RGC who were screened, 3064 patients were included in the analysis (median [IQR] age, 68 [57-77] years; 1764 [57.6%] men). There were 1584 tumors (51.7%) located in the antrum and 1539 stage 2 tumors (50.2%). On multivariable analyses among 1939 patients (owing to 137 patients with missing data for pCR and the exclusion of 988 patients with aCT and aCRT from pCR analysis), nCRT was associated with increased odds of pCR compared with NT, with the greatest odds ratio (OR) among all treatments (OR, 59.55; 95% CI, 10.63-333.56; P < .001). RTTU had the next highest OR (29.96; 95% CI, 2.92-307.53; P = .004). In multivariable analysis for OS among 3061 patients (owing to missing data for OS), CTTU was associated with decreased risk of death compared with NT (hazard ratio, [HR], 0.41; 95% CI, 0.35-0.48; P < .001), with the lowest HR, as was nCRT (HR, 0.48; 95% CI, 0.35-0.66; P < .001), with the next lowest HR. Median OS was greatest among patients treated with CTTU (53.9 months; 95% CI, 44.5-61.0 months), followed by nCRT (39.1 months; 95% CI, 26.9 months-not applicable) and aCT (36.1 months; 95% CI, 28.88-49.18 months), while 2-year OS rates were 65.6% (95% CI, 61.3%-69.5%) for CTTU, 63.6% (95% CI, 52.3%-73.0%) for nCRT, and 59.7% (95% CI, 54.2%-64.7%) for aCT. Conclusions and Relevance: This study found that nCRT was associated with the highest pCR rate, while CTTU (ie, neoadjuvant or adjuvant therapy) was associated with the greatest OS.

Clinical Utility of Olaparib in the Treatment of Metastatic Castration-Resistant Prostate Cancer: A Review of Current Evidence and Patient Selection.

Metastatic castration-resistant prostate cancer (mCRPC) is an aggressive and fatal disease with a median survival of 36 months. With the advent of genetic sequencing to identify individual genomic profiles and acquired tumor-specific pathways, targeted therapies have revolutionized cancer treatment, including the treatment strategy in mCRPC. Poly(adenosine 5'-diphosphate) ribose polymerase inhibitors (PARPi) are oral drugs that target mutations in the homologous recombination repair (HRR) pathway, which are found in approximately 27% of prostate cancer patients. In May 2020, the first PARP inhibitor, olaparib, was approved by the US Food and Drug Administration for men with mCRPC with HHR gene mutations based on the findings of the Phase III PROfound trial that showed improved overall survival in men with mCRPC who received olaparib and whose disease had progressed on a novel hormonal agent. This review summarizes the current evidence and clinical utility of olaparib as treatment in men with mCRPC. We describe the mechanism of action of PARPi, key clinical trials of olaparib in men with mCRPC, and ongoing Phase II and III clinical trials investigating olaparib in combination therapy and as front-line therapy in mCRPC.

The Masquerading, Masculinizing Tumor: A Case Report and Review of the Literature.

Androgen-producing tumors in women are rare neoplasms that can cause secondary virilizing characteristics. Of patients presenting with symptoms of hyperandrogenism, these tumors are found in ∼0.2% of cases. Androgen-producing tumors can arise from the ovary or the adrenal gland. Those arising from the ovary are rare, accounting for <5% of all ovarian tumors. This case presents a hilar Leydig cell tumor of the ovary, which resulted in secondary virilization of a 45-year-old female 2 months after cessation of combined oral contraceptives (COC). Laboratory findings showed markedly elevated total and free testosterone concentrations with normal dehydroepiandrosterone sulfate, however neither pelvic ultrasound nor magnetic resonance imaging demonstrated any masses. Venous sampling under fluoroscopy revealed supraphysiologic testosterone concentrations from the right ovarian vein suggesting the source. The patient underwent bilateral salpingo-oophorectomy revealing a 1.3 cm hilar cell tumor of the right ovary. This article reviews the clinical features, diagnosis, and treatment of hilar Leydig cell tumors and describes the long-term complications of supraphysiologic testosterone levels. As the tumor presented after cessation of COC, we also review the mechanisms by which COC might suppress supraphysiologic androgen levels and mask the secondary virilizing effects of androgen-producing tumors.

Dubin-Johnson Syndrome Presenting During Cardiac Transplantation Evaluation.

Dubin-Johnson syndrome is a rare, benign disorder that results in conjugated hyperbilirubinemia. The disease manifests as intermittent jaundice without long-term hepatic or other clinical complications. This article reports a case of Dubin-Johnson syndrome, which was identified during cardiac transplant evaluation for cardiomyopathy secondary to a polyglycogen storage disease. The patient successfully underwent an orthotopic heart transplant. Postoperatively, her conjugated hyperbilirubinemia increased as compared to her baseline but resolved after several weeks. This report briefly reviews the hepatic manifestations in patients with Dubin-Johnson syndrome undergoing major surgery and highlights urinary coproporphyrin as a useful diagnostic test for Dubin-Johnson syndrome.

Eosinophilic pneumonia: A rare manifestation of amiodarone toxicity diagnosed using traditional bronchoscopy.

Amiodarone is an antiarrhythmic agent used primarily to treat atrial and ventricular arrhythmias. However, the drug also has many adverse effects, including pulmonary toxicity, and a wide range of pulmonary diseases have been reported. Amiodarone-induced eosinophilic pneumonia is a relatively rare adverse effect with an incidence ranging between 5 and 13% [1]. The majority of cases have been diagnosed with lung biopsy, with only one prior reported case diagnosed by bronchoalveolar lavage (BAL) [2]. This report describes the second documented case of amiodarone-induced eosinophilic pneumonia diagnosed by eosinophilia on BAL cytology. In this case, complete cessation of symptoms occurred after discontinuation of amiodarone and treatment with corticosteroids. An updated review of the literature of amiodarone-induced eosinophilic pneumonia is also detailed.