Systemic therapy for hormone receptor-positive/human epidermal growth factor receptor 2-negative early stage and metastatic breast cancer.

Hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer is defined by the presence of the estrogen receptor and/or the progesterone receptor and the absence of HER2 gene amplification. HR-positive/HER2-negative breast cancer accounts for 65%-70% of all breast cancers, and incidence increases with increasing age. Treatment varies by stage, and endocrine therapy is the mainstay of treatment in both early stage and late-stage disease. Combinations with cyclin-dependent kinase 4/6 inhibitors have reduced distant recurrence in the early stage setting and improved overall survival in the metastatic setting. Chemotherapy is used based on stage and tumor biology in the early stage setting and after endocrine resistance for advanced disease. New therapies, including novel endocrine agents and antibody-drug conjugates, are now changing the treatment landscape. With the availability of new treatment options, it is important to define the optimal sequence of treatment to maximize clinical benefit while minimizing toxicity. In this review, the authors first discuss the pathologic and molecular features of HR-positive/HER2-negative breast cancer and mechanisms of endocrine resistance. Then, they discuss current and emerging therapies for both early stage and metastatic HR-positive/HER2-negative breast cancer, including treatment algorithms based on current data.

Where the Sidewalk Ends: Parenting as a Trainee during COVID-19.

Physicians who are also parents have faced significant difficulties during the COVID-19 pandemic. However, most studies of the physician-parent workforce have focused on the experiences of attending physicians. In this commentary, we highlight the ways that trainee parents have uniquely experienced three major stressors during the pandemic: (1) childcare challenges, (2) scheduling difficulties, and (3) career uncertainties. We discuss potential solutions to mitigate these challenges for the future hematology/oncology workforce. As the pandemic continues, we hope that these steps can improve the ability of trainee parents to care both for their patients and their families.

Mutations and karyotype predict treatment response in myelodysplastic syndromes.

We examined the influence of mutations and karyotype on conventional treatment response, specifically hematological improvement in anemia, in primary myelodysplastic syndromes (MDS). Cytogenetic and next generation sequencing (NGS)-derived mutation information was available in 357 patients (median age 74 years; 70% males); the revised international prognostic scoring system risk distribution was very high in 11%, high 15%, intermediate 17%, low 40% and very low 16%. At least one mutation was detected in 81% of patients; most frequent were SF3B1 (32%), ASXL1 (27%), TET2 (24%) and U2AF1 (15%). At median follow-up of 24 months, treatment with hypomethylating agents (HMAs) was documented in 121 (34%) patients, lenalidomide (LEN) in 55 (15%), and erythropoiesis stimulating agents (ESAs) in 136 (38%). ASXL1 mutations adversely affected response to HMAs (27% vs 48%; P = 0.02) and LEN (9% vs 43%; P = 0.04), but not ESAs (P = 0.6). LEN response was also adversely affected by U2AF1 mutations (0% vs 42%; P = 0.02) and high risk karyotype (0% vs 41% in intermediate vs 47% in low risk; P = 0.01). Patients with SF3B1 mutations were more likely to respond to LEN (56% vs 27%; P = 0.04). Contrary to previous reports, we found no association between TET2 mutations and HMA treatment response (40% vs 41%; P = 0.9), even in the absence of ASXL1 mutations (P = 0.4).We conclude that ASXL1 mutations in MDS predict inferior response to treatment with both HMAs and LEN; response to LEN was also compromised by U2AF1 mutations and high risk karyotype; SF3B1 mutations identified patients likely to respond to LEN.

Commentary: Race and Ethnicity in Biomedical Research - Classifications, Challenges, and Future Directions.

The use of race and ethnicity in biomedical research has been a subject of debate for the past three decades. Initially the two major race categories were: White and Black, leaving other minorities uncounted or inappropriately misclassified. As the science of health disparities evolves, more sophisticated and detailed information has been added to large databases. Despite the addition of new racial classifications, including multi-racial denominations, the quality of the data is limited to the data collection process and other social misconceptions. Although race is viewed as an imposed or ascribed status, ethnicity is an achieved status, making it a more challenging variable to include in biomedical research. Ambiguity between race and ethnicity often exists, ultimately affecting the value of both variables. To better understand specific health outcomes or disparities of groups, it is necessary to collect subgroup-specific data. Cultural perceptions and practices, health experiences, and susceptibility to disease vary greatly among broad racial-ethnic groups and requires the collection of nuanced data to understand. Here, we provide an overview of the classification of race and ethnicity in the United States over time, the existing challenges in using race and ethnicity in biomedical research and future research directions.

Targeted next-generation sequencing in myelodysplastic syndromes and prognostic interaction between mutations and IPSS-R.

A 27-gene panel was used for next-generation sequencing (NGS) in 179 patients (median age 73 years) with primary myelodysplastic syndromes (MDS); risk distribution according to the revised International Prognostic Scoring System (IPSS-R) was 11% very high, 18% high, 17% intermediate, 38% low and 16% very low. At least one mutation/variant was detected in 147 (82%) patients; 23% harbored three or more mutations/variants. The most frequent mutations/variants included ASXL1 (30%), TET2 (25%), SF3B1 (20%), U2AF1 (16%), SRSF2 (16%), TP53 (13%), RUNX1 (11%), and DNMT3A (10%). At a median follow up of 30 months, 148 (83%) deaths and 26 (15%) leukemic transformations were recorded. Multivariable analysis of mutations/variants identified ASXL1 (HR 1.7, 95% CI 1.2-2.5), SETBP1 (HR 4.1, 95% CI 1.6-10.2) and TP53 (HR 2.2, 95% CI 1.3-3.4) as risk factors for overall and SRSF2 (HR 3.9, 95% CI 1.5-10.2), IDH2 (HR 3.7, 95% CI 1.2-11.4), and CSF3R (HR 6.0, 95% CI 1.6-22.6) for leukemia-free survival. Addition of age to the multivariable model did not affect these results while accounting for IPSS-R weakened the significance of TP53 mutations/variants (P = .1). An apparently favorable survival impact of SF3B1 mutations was no longer evident after adjustment for IPSS-R. Approximately 41% and 20% of patients harbored at least one adverse mutation/variant for overall and leukemia-free survival, respectively. Number of mutations/variants did not provide additional prognostic value. The survival impact of adverse mutations was most evident in IPSS-R very low/low risk patients. These observations suggest that targeted NGS might assist in treatment decision-making in lower risk MDS.

Parent Penalty: Parental Leave Experiences of Trainees and Early-Career Faculty in Oncology Subspecialties.

PURPOSE: Prime childbearing years occur during medical training and early career, leaving physicians with tough choices between family planning and career growth. Restrictive workplace parental leave (PL) policies may negatively affect physician well-being. We evaluate existing PL and lactation policies, as well as return-to-work experiences, among oncology trainees and early-career faculty. METHODS: An anonymous 43-question cross-sectional survey was distributed via e-mail and social media channels between May and June 2021 to oncology trainees and physicians within 5 years of terminal training in the United States. The survey was administered through SurveyMonkey. Descriptive statistics were used to analyze data. Two hundred seventy-five participants were recruited via social media and outreach to program directors and coordinators in adult hematology/oncology and radiation oncology program directors. RESULTS: The average duration of PL was <6 weeks for most participants. Among those who used PL, 50% felt pressured to work while on PL, 60% felt guilty asking coworkers for help, and 79% were overwhelmed with demands of work and home, whereas only 27% had resources available at workplace to assist with transition back to work. Among those who breastfed at return to work, 31% did not have access to a lactation room, 56% did not have adequate pumping breaks, and 66% did not have pumping breaks mandated in contract. CONCLUSION: Our findings underline the immense magnitude of problems surrounding inadequate PL and support for lactating mothers among trainees and early-career physicians in oncology subspecialities. Policies and practices around PL and lactation should be restructured to meet the needs of the evolving oncology workforce.

Mentorship Experiences Are Not All the Same: A Survey Study of Oncology Trainees and Early-Career Faculty.

PURPOSE: Physician workforce diversity can be a driver of institutional excellence, improving innovation and reducing health disparities. However, the current diversity of the hematology/oncology (HO) workforce does not reflect that of the US population. METHODS: We conducted a cross-sectional online survey of current trainees and faculty within 5 years of completing terminal training in oncology specialties. RESULTS: Of the 306 respondents, 64 (21%) were under-represented in medicine (URiM) and 161 (53%) identified as male. URiM participants were less likely to have a primary mentor (66%) than non-URiM participants (80%; P = .015). Among those who had a primary mentor, URiMs met less frequently (once every 3-6 months or less) with their mentor (19% v 7% non-URiM; P = .003). Furthermore, URiMs were more likely to report having mentors outside their own institution (47% v 40% non-URiM; P = .002) and making compromises to gain access to mentorship (36% v 23% non-URiM; P ≤ 0.001). URiMs were also less likely to apply for grants (34% v 42% non-URiM; P = .035) and awards (28% v 43% non-URiM; P = .019). In multivariable models, URiM individuals were more likely to make compromises to gain access to mentors (odds ratio [OR], 1.96; 95% CI, 1.01 to 3.82) and this remained significant for females (OR, 2.17; 95% CI, 1.26 to 3.75). CONCLUSION: URiM individuals may be less likely to have effective mentorship and apply for awards and grant support. Understanding the challenges of URiM trainees can help shape training environments in academic medicine to ensure that they are grounded in diversity, inclusion, and retention.

Case Report: Clinical Characteristics and Outcomes of HIV Positive Patients With Metastatic Prostate Cancer Treated With Immunotherapy: A Case Series and Literature Review.

Background: The treatment of metastatic prostate cancer has been revolutionized with the advent of many targeted therapies, including immunotherapy. Pembrolizumab has demonstrated benefit in the treatment of certain patients with docetaxel-refractory metastatic castrate-resistant prostate cancer (mCRPC). However, extrapolation of these data to patients with HIV is limited, as these patients are conventionally excluded from therapeutic clinical trials. This study aims to develop a better understanding of the clinical outcomes of HIV positive patients with prostate cancer treated with immunotherapy. A review of the literature is conducted on the use of immunotherapy in HIV positive patients with prostate cancer, and a summary is presented of two clinical cases from a single institution. Methods: This is a retrospective case report of 2 patients diagnosed with prostate cancer and HIV who received treatment with pembrolizumab. Quantitative analysis was performed to summarize patient demographics, clinical history, and outcomes. Results: Two patients with mCRPC and HIV on highly active antiretroviral therapy were identified. Both individuals had biochemical and radiographic response to treatment with pembrolizumab. The duration of response for individual 1 is >31 months and 14 months for individual 2. Neither patient had immune-related adverse events or decreased suppression of their HIV infection. One patient died from disease progression after 14 months of treatment and the other remains on treatment with pembrolizumab to date. Conclusion: In this small case series, pembrolizumab appears to be a safe and effective treatment option for HIV positive patients with metastatic prostate cancer.

Protection of porcine endothelial cells against apoptosis with interleukin-4.

BACKGROUND: Apoptosis is crucial for tissue development and homeostasis, and insufficient apoptosis is pivotal in cancer pathogenesis. Apoptosis may also be important in tissue injury and in this case, it is of interest to induce protection against apoptosis. In organ transplantation, apoptosis has been implicated in acute vascular rejection (AVR); in xenotransplantation, the inducers of apoptosis of relevance in AVR, such as tumor necrosis factor-α (TNF-α), also cause endothelial cell (EC) activation. We have previously shown that interleukin (IL)-4 and IL-13 induced protection in porcine ECs against activation and apoptosis triggered by TNF-α. Now we define signaling processes activated by IL-4 in porcine ECs and mechanisms required for IL-4-induced protection against apoptosis. METHODS: Porcine aortic ECs were used as primary cultures or as virus-induced immortalized cells derived from galactosyl transferase-deficient (Gal(-/-) ) or wild-type pigs. ECs were stimulated with porcine IL-4, either extrinsically or transduced with recombinant adenovirus (adeno) IL-4, and analyzed using immunoblotting. Apoptosis was induced with TNF-α plus cycloheximide and assessed using neutral red uptake or flow cytometry. The role of various signaling proteins in IL-4-induced protection was established using pharmacologic inhibitors and siRNA downregulation of protein expression. RESULTS: IL-4 induced similar degrees of phosphorylation of STAT6 in all 3 types of ECs, and STAT6 was phosphorylated through Jak3. IL-4 induced phosphorylation of Bad through Jak3. Stimulation of ECs with IL-4 caused protection of ECs against apoptosis with an absolute requirement of Jak3/STAT6 activation and major participation of mammalian target of rapamycin complex 2 (mTORC2), Akt, and extracellular signal-regulated kinase 1/2. IL-4 caused no increase in EC levels of protective proteins hemoxygenase-1, inhibitor of apoptosis protein, heat shock protein 70, Bcl-2, and Bcl-xL. ECs transduced with adenoIL-4 exhibited strong and durable protection from apoptosis. Gal(-/-) ECs were as susceptible to induction of protection with IL-4 as wild-type ECs. CONCLUSIONS: IL-4 induces activation of Jak3/STAT6 and phosphorylation of Bad in porcine ECs, ultimately resulting in effective protection of the ECs from apoptosis. Delineation of downstream signals activated by IL-4 that are required for induction of protection suggests possible sites of intervention to design effective therapeutic agents. This is of interest because substances such as IL-4 have pleiotropic effects and cannot be used directly due to potential deleterious effects. Inducing resistance to apoptosis in porcine vascular endothelium may be important to facilitate xenograft survival and accommodation.

Influence of Sociodemographic Factors on Treatment Decisions in Non-Small-Cell Lung Cancer.

INTRODUCTION: In stage IV non-small-cell lung cancer (NSCLC), survival has significantly improved. Despite such trends, it has been noted that patients frequently refuse treatment. Therefore, we explored the factors associated with treatment refusal in NSCLC. PATIENTS AND METHODS: Utilizing the National Cancer Data Base (NCDB), we identified all stage IV NSCLC cases from 2004 to 2014. Patients who received cancer treatment outside of the reporting facility were excluded. Multivariable logistic regression models were used to determine associations with treatment refusal. RESULTS: A total of 341,993 patients were identified; 5.4% of patients refused radiotherapy and 10.3% refused chemotherapy despite provider recommendations. The proportion of patients refusing radiotherapy and chemotherapy increased over time from 4.2% to 7.3% and 7.9% to 15%, respectively (P < .001). In multivariable analysis, men were less likely to refuse treatment compared to women (respectively, odds ratio = 0.80; 95% confidence interval, 0.76-0.84; P < .001; odds ratio = 0.82; 95% confidence interval, 0.80-0.85; P < .001, respectively). Factors associated with radiotherapy refusal included: Medicaid or Medicare as primary insurance, uninsured status, low household median income, and lower educational level. Regarding chemotherapy, uninsured patients, Medicaid patients, and patients with a high comorbidity index were more likely to refuse chemotherapy. Asians had lower rates of chemotherapy refusal relative to non-Hispanic whites. Non-Hispanic whites, Hispanics, and Asians had increasing chemotherapy refusal rates over time, while non-Hispanic blacks had less pronounced trends over time. CONCLUSION: Socioeconomic factors rather than race/ethnicity appear to influence the refusal of cancer treatment in patients with stage IV NSCLC. Assessing socioeconomic challenges should be an essential part of patient evaluation when discussing treatment options.

ERBB2-Low (Also Known as HER2-Low) Breast Cancer.

This JAMA Oncology Patient Page discusses classification of breast cancer and ERBB2 status.

Infectious Complications and Malignancies Arising After Liver Transplantation.

Since the first liver transplant was performed in 1963, great advancements have been made in hepatic transplantation. Surgical techniques have been revised and improved, diagnostic methods for identifying and preventing infections have been developed, and a more conservative use of immunosuppressive agents has resulted in better long-term posttransplant outcomes. A total of 7841 liver transplantations were performed in the United States in 2016, resulting in greater than 85% survival at 1 year posttransplant. However, technical surgical complications, infections, rejections, and chronic medical conditions persist. This article discusses the infectious complications and malignancies that may arise after liver transplantation.

Cardiac melanoma: Retrospective review of a rare disease at the Mayo clinic (1988-2015).

BACKGROUND: Melanoma metastasizing to the heart (cardiac melanoma) is a rare entity that has been described only in autopsy studies or isolated pre-mortem case reports. We aim to better characterize cardiac melanoma, and describe its presenting features, imaging findings, and disease course with a case series collected over nearly 30years. METHODS: We performed a retrospective review of all patients diagnosed with cardiac melanoma at the Mayo Clinic from 1988 to 2015. Qualitative analysis was performed on patient demographics, clinical history, and imaging modalities. RESULTS: 11 patients (7 male, median age 63years) were identified with cardiac melanoma. Shortness of breath (64%) was the most common presenting symptom. Transthoracic echocardiography (TTE) was utilized in the assessment of all patients though it failed to identify 20% of masses that were seen on fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) or cardiac magnetic resonance (CMR). The majority of masses were located within the cardiac chambers (46% right atrium, 18% right ventricle, 18% left atrium), and 36% appeared mobile on TTE. Patients lived for a median of 68months (interquartile range [IQR] 14-143months) after the initial diagnosis of primary melanoma, and only 12months (IQR 2-150months) after diagnosis of cardiac melanoma. CONCLUSION: Echocardiography can generally identify most cases of cardiac melanoma, though it misses one-fifth of masses seen on FDG PET/CT or CMR. Cardiac melanoma is associated with a poor prognosis.