Frequent upregulation of HER2 protein in hormone-receptor-positive HER2-negative breast cancer after short-term neoadjuvant endocrine therapy.

BACKGROUND: Endocrine resistant metastatic disease develops in ~ 20-25% of hormone-receptor-positive (HR+) breast cancer (BC) patients despite endocrine therapy (ET) use. Upregulation of HER family receptor tyrosine kinases (RTKs) represent escape mechanisms in response to ET in some HR+ tumors. Short-term neoadjuvant ET (NET) offers the opportunity to identify early endocrine escape mechanisms initiated in individual tumors. METHODS: This was a single arm, interventional phase II clinical trial evaluating 4 weeks (± 1 week) of NET in patients with early-stage HR+/HER2-negative (HER2-) BC. The primary objective was to assess NET-induced changes in HER1-4 proteins by immunohistochemistry (IHC) score. Protein upregulation was defined as an increase of ≥ 1 in IHC score following NET. RESULTS: Thirty-seven patients with cT1-T3, cN0, HR+/HER2- BC were enrolled. In 35 patients with evaluable tumor HER protein after NET, HER2 was upregulated in 48.6% (17/35; p = 0.025), with HER2-positive status (IHC 3+ or FISH-amplified) detected in three patients at surgery, who were recommended adjuvant trastuzumab-based therapy. Downregulation of HER3 and/or HER4 protein was detected in 54.2% of tumors, whereas HER1 protein remained low and unchanged in all cases. While no significant volumetric reduction was detected radiographically after short-term NET, significant reduction in tumor proliferation rates were observed. No significant associations were identified between any clinicopathologic covariates and changes in HER1-4 protein expression on multivariable analysis. CONCLUSION: Short-term NET frequently and preferentially upregulates HER2 over other HER family RTKs in early-stage HR+/HER2- BC and may be a promising strategy to identify tumors that utilize HER2 as an early endocrine escape pathway. CLINICAL TRIAL REGISTRY: Trial registration number: NCT03219476.

Matched Case Control Analysis of Breast Cancer- Specific Factors Affecting Risk of Developing SARS-CoV-2 Infection.

INTRODUCTION: In this retrospective matched case control study, we aim to identify breast cancer-related risk factors associated with developing COVID-19 and describe outcomes of patients with breast cancer diagnosed with COVID-19. METHODS: Women with breast cancer treated at the Medical College of Wisconsin and diagnosed with COVID-19 from March through December 2020 served as cases, and those without COVID-19 within the same timeframe served as controls. Univariate and multivariate comparisons were performed. RESULTS: Twenty-five cases and 77 controls were identified. All cases were fully matched by age, obesity, county, and race. Mean age was 54.6 versus 54.9, body mass index 31.0 versus 31.6, 48% lived in Milwaukee County, and 68% were White. Regarding COVID-19 outcomes, 24.0% (n = 6) of cases were hospitalized, median length of stay was 2 days, 8% (n=2) needed oxygen, 4% (n = 6) were intubated, and 4% (n = 6) died. COVID-19 led to treatment delays in 40% of cases. On univariate analysis, there was no statistically significant difference in hormone receptor status or breast cancer stage. Being on active chemotherapy (OR 5.8, P = 0.043) significantly increased the likelihood of developing COVID-19. CONCLUSIONS: In this matched case control study of patients with breast cancer, active chemotherapy was significantly associated with an increased likelihood of developing COVID-19, with a trend seen for triple negative disease. These findings support continued strict precautions for those on active chemotherapy and warrant further analysis in those with triple negative disease.

Frequent Upregulation Of HER2 Protein In Hormone Receptor-Positive HER2-Negative Breast Cancer After Short-Term Neoadjuvant Endocrine Therapy.

Background. Endocrine resistant metastatic disease develops in ~20-25% of hormone-receptor positive (HR+) breast cancer (BC) patients despite endocrine therapy (ET) use. Upregulation of HER family receptor tyrosine kinases (RTKs) represent escape mechanisms in response to ET in some HR+ tumors. Short-term neoadjuvant ET (NET) offers the opportunity to identify early endocrine escape mechanisms initiated in individual tumors. Methods. This was a single arm, interventional phase II clinical trial evaluating 4 weeks (+/-1 week) of NET in patients with early-stage HR+/HER2-negative (HER2-) BC. The primary objective was to assess NET-induced changes in HER1-4 proteins by immunohistochemistry (IHC) score. Protein upregulation was defined as an increase of ≥1 in IHC score following NET. Results. Thirty-seven patients with cT1-T3, cN0, HR+/HER2- BC were enrolled. In 35 patients with evaluable tumor HER protein after NET, HER2 was upregulated in 48.6% (17/35; p=0.025), with HER2-positive status (IHC 3+ or FISH-amplified) detected in three patients at surgery, who were recommended adjuvant trastuzumab-based therapy. Downregulation of HER3 and/or HER4 protein was detected in 54.2% of tumors, whereas HER1 protein remained low and unchanged in all cases. While no significant volumetric reduction was detected radiographically after short-term NET, significant reduction in tumor proliferation rates were observed. No significant associations were identified between any clinicopathologic covariates and changes in HER1-4 protein expression on multivariable analysis. Conclusion . Short-term NET frequently and preferentially upregulates HER2 over other HER-family RTKs in early-stage HR+/HER2- BC and may be a promising strategy to identify tumors that utilize HER2 as an early endocrine escape pathway. Trial registration number: NCT03219476 Date of registration for prospectively registered trials: July 17, 2017.

Androgen receptor expression in patients with triple negative breast cancer treated with neoadjuvant chemotherapy: a single institution study.

Background: Androgen receptor (AR) expression has emerged as a potential prognostic and predictive marker in patients with triple negative breast cancer (TNBC). We conducted a retrospective analysis to evaluate pathologic complete response (pCR) rates, disease-free survival (DFS) and overall survival (OS) in patients with AR positive and AR negative TNBC treated with neoadjuvant chemotherapy. Methods: 107 patients with TNBC subtype, treated with neoadjuvant chemotherapy between June 2006 and March 2016 were evaluated for AR expression. Androgen receptors were evaluated by immunohistochemical staining (clone AR441, Dilution 1:50, Dako-Agilent, Santa Clara, CA) using whole tissue sections from archived paraffin-embedded formalin-fixed (FFPE) blocks. AR positive was defined as ≥10% nuclear stained cells. Correlation of AR expression was examined with age, BMI, race, menopausal status, tumor grade, tumor size, and lymph node involvement, and response and outcomes. Univariate and multivariate analyses were performed to determine an association with AR expression and pathologic response and survival outcomes. Results: Fifty-eight patients with available tumor specimens were stained, with twenty (34.5%) being AR-positive and thirty-eight (65.5%) being AR negative. Median age was 49 years and median follow up was 5.7 years. All patients received anthracycline based neoadjuvant chemotherapy with 13 patients (23%) receiving an additional platinum chemotherapy. BRCA mutation positivity was 7% for the entire group. No differences in age, menopausal status, BMI, race, tumor size and lymph node involvement were observed between the two groups. However, there was a statistically significant difference in tumor grade between the two groups (p=0.008). Overall pCR rate was 28% with no difference between the two groups (30% vs 26%, p=0.56). There was no statistically significant difference in median DFS (5.9 years vs 5.2 years (p=0.94) and median OS (6.2 years vs 5.4 years, p=0.98) between the AR positive and AR negative groups. Conclusions: Our study did not find an association of AR status and the pathologic responses or survival outcomes in patients with TNBC treated with neoadjuvant chemotherapy. Further studies exploring the prognostic and predictive role of AR in patients with TNBC are warranted.

Long-Term Outcomes of Dose-Escalated Pelvic Lymph Node Intensity-Modulated Radiation Therapy (IMRT) With a Simultaneous Hypofractionated Boost to the Prostate for Very High-Risk Adenocarcinoma of the Prostate: A Prospective Phase II Clinical Trial.

PURPOSE: There remains limited data as to the feasibility, safety, and efficacy of higher doses of elective radiation therapy to the pelvic lymph nodes in men with high-risk prostate cancer. We conducted a phase II study to evaluate moderate dose escalation to the pelvic lymph nodes using a simultaneous integrated boost to the prostate. METHODS AND MATERIALS: Patients were eligible with biopsy-proven adenocarcinoma of the prostate, a calculated lymph node risk of at least 25%, Karnofsky performance scale ≥70, and no evidence of M1 disease. Acute and late toxicity were prospectively collected at each follow-up using Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0). The pelvic lymph nodes were treated to a dose of 56 Gy over 28 fractions with a simultaneous integrated boost to the prostate to a total dose of 70 Gy over 28 fractions using intensity-modulated radiation therapy. RESULTS: Thirty patients were prospectively enrolled from October 2010 to August 2014. Median patient age was 70 years (57-83), pretreatment prostate-specific antigen was 11.5 ng/mL (3.23-111.5), T stage was T2c (T1c-T3b), and Gleason score was 9 (6-9). CTCAE v4.0 rate of any grade 1 or 2 genitourinary and gastrointestinal toxicity were 55% and 44%, respectively, and there was 1 reported acute grade 3 genitourinary and gastrointestinal toxicity, both unrelated to protocol therapy. With a median follow-up of 6.4 years, the biochemical failure free survival rate was 80.2%, and mean biochemical progression free survival was 8.3 years (95% confidence interval [CI], 7.2-9.4). The prostate cancer specific survival was 95.2%, and mean prostate cancer specific survival was 8.7 years (95% CI, 8.0-9.4). Five-year distant metastases free survival was 96%. Medians were not reached. CONCLUSIONS: In this single arm, small, prospective feasibility study, nodal radiation therapy dose escalation was safe, feasible, and seemingly well tolerated. Rates of progression free survival are highly encouraging in this population of predominately National Comprehensive Cancer Network very high-risk patients.