Poziotinib treatment in patients with HER2-positive advanced breast cancer who have received prior anti-HER2 regimens.

PURPOSE: Poziotinib is an irreversible pan-inhibitor of the human epidermal growth factor receptor (HER) that has shown acceptable tolerability and antitumor activity in phase I and II trials in patients with advanced solid tumors. In the present open-label, multicenter phase II study, we demonstrate safety, tolerability, and preliminary efficacy data from two different dosing schedules in patients with HER2-positive advanced breast cancer. PATIENTS AND METHODS: Patients who had received at least two prior HER2-directed therapy lines for advanced disease, received 24 mg poziotinib on an intermittent dosing schedule (cohort 1) or 16 mg poziotinib once daily on a continuous dosing schedule (cohort 2). The primary endpoint was overall response rate (ORR). Secondary endpoints were progression-free survival (PFS), disease control rate (DCR), and time to progression (TTP). Secondary endpoints additionally included safety and pharmacokinetics. RESULTS: A total of 67 patients were enrolled. The ORR was 30% in both groups (p = 0.98). DCR was 60% vs 78% (p = 0.15) and median PFS and TTP were 4.1 vs 4.9 months (both p = 0.30) for cohorts 1 and 2, respectively. The most common treatment related adverse events (AEs) of any grade included diarrhea (88% vs 85%, p = 0.76), rash (88% vs 88%, p = 0.96), and stomatitis (64% vs 56%, p = 0.52), with grade 3-4 diarrhea occurring in 33% vs 32% of patients (p = 0.93) and grade 3-4 rash in 27% vs 35% of patients (p = 0.48) in cohort 1 vs cohort 2, respectively. CONCLUSION: Poziotinib demonstrated evidence of clinical activity in patients with pre-treated HER2-positive advanced breast cancer, although high levels of toxicity may preclude further studies at this time.

mTOR inhibition abrogates human mammary stem cells and early breast cancer progression markers.

BACKGROUND: Mammary physiology is distinguished in containing adult stem/progenitor cells that are actively amending the breast tissue throughout the reproductive lifespan of women. Despite their importance in both mammary gland development, physiological maintenance, and reproduction, the exact role of mammary stem/progenitor cells in mammary tumorigenesis has not been fully elucidated in humans or animal models. The implications of modulating adult stem/progenitor cells in women could lead to a better understanding of not only their function, but also toward possible breast cancer prevention led us to evaluate the efficacy of rapamycin in reducing mammary stem/progenitor cell activity and malignant progression markers. METHODS: We analyzed a large number of human breast tissues for their basal and luminal cell composition with flow cytometry and their stem and progenitor cell function with sphere formation assay with respect to age and menopausal status in connection with a clinical study (NCT02642094) involving a low-dose (2 mg/day) and short-term (5-7 days) treatment of the mTOR inhibitor sirolimus. The expression of biomarkers in biopsies and surgical breast samples were measured with quantitative analysis of immunohistochemistry. RESULTS: Sirolimus treatment significantly abrogated mammary stem cell activity, particularly in postmenopausal patients. It did not affect the frequency of luminal progenitors but decreased their self-renewal capacity. While sirolimus had no effect on basal cell population, it decreased luminal cell population, particularly in postmenopausal patients. It also significantly diminished prognostic biomarkers associated with breast cancer progression from ductal carcinoma in situ to invasive breast cancer including p16INK4A, COX-2, and Ki67, as well as markers of the senescence-associated secretary phenotype, thereby possibly functioning in preventing early breast cancer progression. CONCLUSION: Overall, these findings indicate a link from mTOR signaling to mammary stem and progenitor cell activity and cancer progression. Trial registration This study involves a clinical trial registered under the ClinicalTrials.gov identifier NCT02642094 registered December 30, 2015.

Student Perspectives on the Undergraduate Medical Student Research Experience at a Single United States Allopathic Institution.

Introduction The purpose of this study was to identify student-reported institutional facilitators and barriers to successful research experiences at a single United States allopathic institution. Residency applications have increasingly become more competitive, and with the United States Medical Licensing Examination (USMLE) Step 1 exam's transition to pass/fail, factors such as research experience and outcomes may become more important to increase residency application competitiveness. This study sought to explore factors that impact successful research experiences leading to tangible outcomes for medical students at our medical school, the Joe R. & Teresa Lozano Long School of Medicine. Methods  A cross-sectional survey was developed and administered via REDCap to 853 students in May 2022. Survey question domains included demographics, past and present research participation, perceived barriers/facilitators to research, tangible outcomes (e.g., publications and posters), and overall satisfaction with research comparing subjectively "best" and "worst" experiences. The Institutional Review Board (IRB) deemed this project as non-regulated research.  Results We had a 24% (n = 204/853) response rate. The responses were distributed equally among the four classes. A big portion of the participants (71%, n = 59/83) identified a tangible outcome as the most important measure of success. Regarding facilitators, students identified having a mentor (89%, n = 165/184) and departmental connections (85%, n = 156/184) as the most important when looking for a project. Barriers included SMART goals (Specific, Measurable, Achievable, Relevant, and Time-Bound) lacking in 31% (n = 24/75) of worst projects, followed by a clear timeline in 29% (n = 22/76) and hours of commitment in 27% (n = 21/78). The best projects were more likely to have resulted in a publication (61% (27/44) vs. 32% (14/44)) or have a poster (64% (28/44) vs. 36% (16/44)). Conclusions Medical students are interested in participating in research, with important facilitators including mentorship and departmental connections. Modifiable variables include lack of clear timelines, well-defined roles and responsibilities, and time commitments. This information may be useful for faculty who mentor medical students or medical schools interested in designing medical student research programs.

Clinical Characteristics, Racial Inequities, and Outcomes in Patients with Breast Cancer and COVID-19: A COVID-19 and Cancer Consortium (CCC19) Cohort Study.

Background: Limited information is available for patients with breast cancer (BC) and coronavirus disease 2019 (COVID-19), especially among underrepresented racial/ethnic populations. Methods: This is a COVID-19 and Cancer Consortium (CCC19) registry-based retrospective cohort study of females with active or history of BC and laboratory-confirmed severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection diagnosed between March 2020 and June 2021 in the US. Primary outcome was COVID-19 severity measured on a five-level ordinal scale, including none of the following complications, hospitalization, intensive care unit admission, mechanical ventilation, and all-cause mortality. Multivariable ordinal logistic regression model identified characteristics associated with COVID-19 severity. Results: 1,383 female patient records with BC and COVID-19 were included in the analysis, the median age was 61 years, and median follow-up was 90 days. Multivariable analysis revealed higher odds of COVID-19 severity for older age (aOR per decade, 1.48 [95% CI, 1.32 - 1.67]); Black patients (aOR 1.74; 95 CI 1.24-2.45), Asian Americans and Pacific Islander patients (aOR 3.40; 95 CI 1.70 - 6.79) and Other (aOR 2.97; 95 CI 1.71-5.17) racial/ethnic groups; worse ECOG performance status (ECOG PS ≥2: aOR, 7.78 [95% CI, 4.83 - 12.5]); pre-existing cardiovascular (aOR, 2.26 [95% CI, 1.63 - 3.15])/pulmonary comorbidities (aOR, 1.65 [95% CI, 1.20 - 2.29]); diabetes mellitus (aOR, 2.25 [95% CI, 1.66 - 3.04]); and active and progressing cancer (aOR, 12.5 [95% CI, 6.89 - 22.6]). Hispanic ethnicity, timing and type of anti-cancer therapy modalities were not significantly associated with worse COVID-19 outcomes. The total all-cause mortality and hospitalization rate for the entire cohort was 9% and 37%, respectively however, it varied according to the BC disease status. Conclusions: Using one of the largest registries on cancer and COVID-19, we identified patient and BC related factors associated with worse COVID-19 outcomes. After adjusting for baseline characteristics, underrepresented racial/ethnic patients experienced worse outcomes compared to Non-Hispanic White patients.

Clinical characteristics, racial inequities, and outcomes in patients with breast cancer and COVID-19: A COVID-19 and cancer consortium (CCC19) cohort study.

Background: Limited information is available for patients with breast cancer (BC) and coronavirus disease 2019 (COVID-19), especially among underrepresented racial/ethnic populations. Methods: This is a COVID-19 and Cancer Consortium (CCC19) registry-based retrospective cohort study of females with active or history of BC and laboratory-confirmed severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection diagnosed between March 2020 and June 2021 in the US. Primary outcome was COVID-19 severity measured on a five-level ordinal scale, including none of the following complications, hospitalization, intensive care unit admission, mechanical ventilation, and all-cause mortality. Multivariable ordinal logistic regression model identified characteristics associated with COVID-19 severity. Results: 1383 female patient records with BC and COVID-19 were included in the analysis, the median age was 61 years, and median follow-up was 90 days. Multivariable analysis revealed higher odds of COVID-19 severity for older age (aOR per decade, 1.48 [95% CI, 1.32-1.67]); Black patients (aOR 1.74; 95 CI 1.24-2.45), Asian Americans and Pacific Islander patients (aOR 3.40; 95 CI 1.70-6.79) and Other (aOR 2.97; 95 CI 1.71-5.17) racial/ethnic groups; worse ECOG performance status (ECOG PS ≥2: aOR, 7.78 [95% CI, 4.83-12.5]); pre-existing cardiovascular (aOR, 2.26 [95% CI, 1.63-3.15])/pulmonary comorbidities (aOR, 1.65 [95% CI, 1.20-2.29]); diabetes mellitus (aOR, 2.25 [95% CI, 1.66-3.04]); and active and progressing cancer (aOR, 12.5 [95% CI, 6.89-22.6]). Hispanic ethnicity, timing, and type of anti-cancer therapy modalities were not significantly associated with worse COVID-19 outcomes. The total all-cause mortality and hospitalization rate for the entire cohort was 9% and 37%, respectively however, it varied according to the BC disease status. Conclusions: Using one of the largest registries on cancer and COVID-19, we identified patient and BC-related factors associated with worse COVID-19 outcomes. After adjusting for baseline characteristics, underrepresented racial/ethnic patients experienced worse outcomes compared to non-Hispanic White patients. Funding: This study was partly supported by National Cancer Institute grant number P30 CA068485 to Tianyi Sun, Sanjay Mishra, Benjamin French, Jeremy L Warner; P30-CA046592 to Christopher R Friese; P30 CA023100 for Rana R McKay; P30-CA054174 for Pankil K Shah and Dimpy P Shah; KL2 TR002646 for Pankil Shah and the American Cancer Society and Hope Foundation for Cancer Research (MRSG-16-152-01-CCE) and P30-CA054174 for Dimpy P Shah. REDCap is developed and supported by Vanderbilt Institute for Clinical and Translational Research grant support (UL1 TR000445 from NCATS/NIH). The funding sources had no role in the writing of the manuscript or the decision to submit it for publication. Clinical trial number: CCC19 registry is registered on ClinicalTrials.gov, NCT04354701.

Immunogenicity of SARS-CoV-2 messenger RNA vaccines in patients with cancer.

Patients with cancer experience a higher burden of SARS-CoV-2 infection, disease severity, complications, and mortality, than the general population. SARS-CoV-2 mRNA vaccines are highly effective in the general population; however, few data are available on their efficacy in patients with cancer. Using a prospective cohort, we assessed the seroconversion rates and anti-SARS-CoV-2 spike protein antibody titers following the first and second dose of BNT162b2 and mRNA-1273 SARS-CoV-2 vaccines in patients with cancer in US and Europe from January to April 2021. Among 131 patients, most (94%) achieved seroconversion after receipt of two vaccine doses. Seroconversion rates and antibody titers in patients with hematological malignancy were significantly lower than those with solid tumors. None of the patients with history of anti-CD-20 antibody in the 6 months before vaccination developed antibody response. Antibody titers were highest for clinical surveillance or endocrine therapy groups and lowest for cytotoxic chemotherapy or monoclonal antibody groups.

ERα-related chromothripsis enhances concordant gene transcription on chromosome 17q11.1-q24.1 in luminal breast cancer.

BACKGROUND: Chromothripsis is an event of genomic instability leading to complex chromosomal alterations in cancer. Frequent long-range chromatin interactions between transcription factors (TFs) and targets may promote extensive translocations and copy-number alterations in proximal contact regions through inappropriate DNA stitching. Although studies have proposed models to explain the initiation of chromothripsis, few discussed how TFs influence this process for tumor progression. METHODS: This study focused on genomic alterations in amplification associated regions within chromosome 17. Inter-/intra-chromosomal rearrangements were analyzed using whole genome sequencing data of breast tumors in the Cancer Genome Atlas (TCGA) cohort. Common ERα binding sites were defined based on MCF-7, T47D, and MDA-MB-134 breast cancer cell lines using univariate K-means clustering methods. Nanopore sequencing technology was applied to validate frequent rearrangements detected between ATC loci on 17q23 and an ERα hub on 20q13. The efficacy of pharmacological inhibition of a potentially druggable target gene on 17q23 was evaluated using breast cancer cell lines and patient-derived circulating breast tumor cells. RESULTS: There are five adjoining regions from 17q11.1 to 17q24.1 being hotspots of chromothripsis. Inter-/intra-chromosomal rearrangements of these regions occurred more frequently in ERα-positive tumors than in ERα-negative tumors. In addition, the locations of the rearrangements were often mapped within or close to dense ERα binding sites localized on these five 17q regions or other chromosomes. This chromothriptic event was linked to concordant upregulation of 96 loci that predominantly regulate cell-cycle machineries in advanced luminal tumors. Genome-editing analysis confirmed that an ERα hub localized on 20q13 coordinately regulates a subset of these loci localized on 17q23 through long-range chromosome interactions. One of these loci, Tousled Like Kinase 2 (TLK2) known to participate in DNA damage checkpoint control, is an actionable target using phenothiazine antipsychotics (PTZs). The antiproliferative effect of PTZs was prominent in high TLK2-expressing cells, compared to low expressing cells. CONCLUSION: This study demonstrates a new approach for identifying tumorigenic drivers from genomic regions highly susceptible to ERα-related chromothripsis. We found a group of luminal breast tumors displaying 17q-related chromothripsis for which antipsychotics can be repurposed as treatment adjuncts.

Tyrosine phosphorylation regulates ERß ubiquitination, protein turnover, and inhibition of breast cancer.

Unlike estrogen receptor α (ERα) that predominantly promotes hormone-dependent breast tumor growth, ERß exhibits antitumor effects in a variety of cancer types. We recently identified a phosphotyrosine residue in ERß, but not ERα, that dictates ERß transcriptional activity and antitumor function. We show here that this ER isotype-specific phosphotyrosine switch is important for regulating ERß activity in cell proliferation, migration, and invasion. At the mechanistic level, phosphorylated ERß, which recruits transcriptional coactivator p300, is in turn targeted by p300 for ubiquitination and proteasome-dependent protein turnover. Furthermore, ERß-specific agonists such as S-equol enhance ERß phosphorylation, suggesting a crosstalk between ligand- and posttranslational modification-dependent ERß activation. Inhibition of xenograft tumor growth by S-equol is associated with reduced tumor Ki-67 expression and elevated ERß tyrosine phosphorylation. Taken together, our data support the notion that phosphotyrosine-dependent ERß signaling is an attractive target for anticancer treatment.

Use of Milestones and Development of Entrustable Professional Activities in 2 Hematology/Oncology Training Programs.

BACKGROUND: The Next Accreditation System (NAS) increases the focus on educational outcomes and meaningful evaluation of learners. This requires that key clinical faculty develop new assessment formats such as entrustable professional activities (EPAs). OBJECTIVES: To build and develop milestone-based assessment tools supporting 5 EPAs for a hematology/oncology fellow continuity clinic, and to educate key clinical faculty regarding the Clinical Competency Committee (CCC) and the NAS. METHODS: Program directors from 2 hematology/oncology fellowship programs developed 5 EPAs for continuity clinic evaluation supported by milestone-based assessment. The program directors met to create a unified CCC charter. Key clinical faculty helped to develop a milestone-based evaluation of fellow continuity clinic through creation of 5 hematology/oncology-specific EPAs. Formal entrustment regarding EPAs was deliberated by the CCC. RESULTS: A total of 18 fellows were evaluated. Clinical Competency Committee deliberation at each institution took approximately 10 minutes per fellow for discussion and decision regarding entrustment for all 5 EPAs supporting continuity clinic. One-third of postgraduate year (PGY)-4s, 50% of PGY-5s, and 100% of PGY-6s were deemed competent in all 5 EPAs by the CCC. CONCLUSIONS: All hematology/oncology trainees in San Antonio were evaluated using milestone-based assessment for continuity clinic, and entrustment decisions regarding 5 EPAs were made by the CCC. This project may provide other programs with a sound basis for adoption and further development of the next generation of evaluation tools at their institutions. Entrustable professional activities that are rotation specific should be used as a starting point for linking to the competencies, subcompetencies, and the reporting milestones.

Breast cancer treatment delays in a majority minority community: is there a difference?

PURPOSE: Recent studies from large nationwide cancer databases have consistently shown that Hispanic women with breast cancer have delays in treatment initiation compared with non-Hispanic white women. However, time to treatment initiation has not been studied in a community where Hispanics are the majority. PATIENTS AND METHODS: We conducted a retrospective, observational study of 362 female patients with breast cancer treated at a large National Cancer Institute (NCI) -designated cancer center with a largely Hispanic population. We examined the relationship between race/ethnicity and time from mammogram to biopsy as well as time from biopsy to treatment initiation using Kaplan-Meier analyses and multivariable Cox proportional hazards regression. RESULTS: Half of the female patients with breast cancer were of Hispanic descent (50.0%; n = 181). Hispanic patients were more likely to be obese, have an Eastern Cooperative Oncology Group functional status ≥ 1, and have higher histologic grade disease (all P ≤ .05); no differences in American Joint Committee on Cancer stage at diagnosis were observed. After comprehensive adjustment for demographic and clinical characteristics, we found no significant differences between Hispanic versus non-Hispanic white patients in time from mammogram to biopsy (hazard ratio [HR], 0.91; 95% CI, 0.68 to 1.21) or time from biopsy to treatment (HR, 1.13; 95% CI, 0.69 to 1.88). CONCLUSION: Hispanic women and Non-Hispanic white women with breast cancer treated at an NCI-designated cancer center had similar times to biopsy and treatment initiation. These findings suggest that in majority minority communities with large cancer centers, racial disparities can be reduced. With a growing Hispanic population throughout the United States, future studies should examine the long-term impact on improved breast cancer survival in this population.