Emerging evidence suggests that the novel Coronavirus disease-2019 (COVID-19) is deadlier for men than women both in China and in Europe. Male sex is a risk factor for COVID-19 mortality. The meccanisms underlying the reduced morbidity and lethality in women are currently unclear, even though hypotheses have been posed (Brandi and Giustina in Trends Endocrinol Metab. 31:918-27, 2020). This article aims to describe the role of sex hormones in sex- and gender-related fatality of COVID-19. We discuss the possibility that potential sex-specific mechanisms modulating the course of the disease include both the androgen- and the estrogen-response cascade. Sex hormones regulate the respiratory function, the innate and adaptive immune responses, the immunoaging, the cardiovascular system, and the entrance of the virus in the cells. Recommendations for the future government policies and for the management of COVID-19 patients should include a dimorphic approach for males and females. As the estrogen receptor signaling appears critical for protection in women, more studies are needed to translate the basic knowledge into clinical actions. Understanding the etiological bases of sexual dimorphism in COVID-19 could help develop more effective strategies in individual patients in both sexes, including designing a good vaccine.

Are sex hormones promising candidates to explain sex disparities in the COVID-19 pandemic?

The coronavirus disease 2019 (COVID-19) pandemic has resulted in rapid and regionally different approaches to breast cancer care.
 In order to evaluate these changes, a COVID-19-specific registry was developed within the American Society of Breast Surgeons (ASBrS) Mastery that tracked whether decisions were usual or modified for COVID-19. Data on patient care entered into the COVID-19-specific registry and the ASBrS Mastery registry from 1 March 2020 to 15 March 2021 were reviewed.
 Overall, 177 surgeons entered demographic and treatment data on 2791 patients. Mean patient age was 62.7 years and 9.0% (252) were of African American race. Initial consultation occurred via telehealth in 6.2% (173) of patients and 1.4% (40) developed COVID-19. Mean invasive tumor size was 2.1 cm and 17.8% (411) were node-positive. In estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER+/HER2−) disease, neoadjuvant endocrine therapy (NET) was used as the usual approach in 6.9% (119) of patients and due to COVID-19 in an additional 31% (542) of patients. Patients were more likely to receive NET due to COVID-19 with increasing age and if they lived in the Northeast or Southeast (odds ratio [OR] 1.1, 2.3, and 1.7, respectively; p < 0.05). Genomic testing was performed on 51.5% (781) of estrogen-positive patients, of whom 20.7% (162) had testing on the core due to COVID-19. Patients were less likely to have core biopsy genomic testing due to COVID-19 if they were older (OR 0.89; p = 0.01) and more likely if they were node-positive (OR 4.0; p < 0.05). A change in surgical approach due to COVID-19 was reported for 5.4% (151) of patients. The ASBrS COVID-19 registry provided a platform for monitoring treatment changes due to the pandemic, highlighting the increased use of NET.

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Analysis of the Impact of the COVID-19 Pandemic on the Multidisciplinary Management of Breast Cancer: Review from the American Society of Breast Surgeons COVID-19 and Mastery Registries.

Neoadjuvant chemotherapy (NCT) is considered more effective in downstaging hormone receptor-positive (HR+) breast cancer than neoadjuvant endocrine therapy (NET), particularly in node-positive disease. This study compared breast and axillary response and survival after NCT and NET in HR+ breast cancer. Based on American College of Surgeons Oncology Group (ACOSOG) Z1031 criteria, women age 50 years or older with cT2-4 HR+ breast cancer who underwent NET or NCT and surgery were identified in the National Cancer Database 2010–2016. Chi-square and logistic regression analysis determined differences between the NCT and NET groups and therapy response, including downstaging and pathologic complete response (pCR, ypT0/is and ypN0). Of 19,829 patients, 14,025 (70.7%) received NCT and 5804 (29.3%) received NET. The NET patients were older (mean age, 68.9 vs. 60.3; P < 0.001) and had greater comorbidity (1+ Charlson–Deyo score, 21% vs. 16%; P < 0.001). Therapy achieved T downstaging (any) for 58% of the patients with NCT versus 40.5% of the patients with NET, and in-breast pCR was achieved for 9.3% of the NCT versus 1.3% of the NET patients (P < 0.001). Approximately half of the mastectomy procedures could have been potentially avoided for the patients with in-breast pCR (53.6% of the NCT and 43.8% of the NET patients). For the cN+ patients, N downstaging (any) was 29% for the NCT patients versus 18.3% for the NET patients (P < 0.001), and nodal pCR was achieved for 20.3% of the NCT versus 13.5% of the NET patients (P < 0.001). Among those with nodal pCR, axillary lymph node dissection (ALND) still was performed for 56% of the patients after NCT and 45% of the patients after NET. Although the response rates after NCT were higher, NET achieved both T and N downstaging and pCR. Neoadjuvant endocrine therapy can be used to de-escalate surgery for patients who cannot tolerate NCT or when chemotherapy may not be effective based on genomic testing.

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Neoadjuvant Endocrine Therapy as an Alternative to Neoadjuvant Chemotherapy Among Hormone Receptor-Positive Breast Cancer Patients: Pathologic and Surgical Outcomes.

Key Points Question Did the use of neoadjuvant-intent systemic therapy for patients with breast cancer change after the emergence of COVID-19 in Ontario, Canada? Findings In this cohort study including 10 920 patients, the use of neoadjuvant-intent chemotherapy and hormonal treatment increased during the COVID-19 era, but there was substantial regional variability. Bridging hormonal therapy was a more common adaptation to cancer treatment in the COVID-19 era than neoadjuvant chemotherapy; neoadjuvant-intent systemic treatment was not associated with short-term outcomes in the COVID-19 era. Meaning These findings suggest that patients with breast cancer were more likely to receive neoadjuvant-intent systemic treatment in the COVID-19 era to offset delays in surgical capacity.

https://doi.org/10.1001/jamanetworkopen.2022.25118

Comparison of Use of Neoadjuvant Systemic Treatment for Breast Cancer and Short-term Outcomes Before vs During the COVID-19 Era in Ontario, Canada

The early months of the COVID-19 pandemic led to reduced cancer screenings and delayed cancer surgeries. We used insurance claims data to understand how breast cancer incidence and treatment after diagnosis changed nationwide over the course of the pandemic. Using the Optum Research Database from January 2017 to March 2021, including approximately 19 million US adults with commercial health insurance, we identified new breast cancer diagnoses and first treatment after diagnosis. We compared breast cancer incidence and proportion of newly diagnosed patients receiving pre-operative systemic therapy pre-COVID, in the first 2 months of the COVID pandemic and in the later part of the COVID pandemic. Average monthly breast cancer incidence was 19.3 (95% CI 19.1–19.5) cases per 100,000 women and men pre-COVID, 11.6 (95% CI 10.8–12.4) per 100,000 in April–May 2020, and 19.7 (95% CI 19.3–20.1) per 100,000 in June 2020–February 2021. Use of pre-operative systemic therapy was 12.0% (11.7–12.4) pre-COVID, 37.7% (34.9–40.7) for patients diagnosed March–April 2020, and 14.8% (14.0–15.7) for patients diagnosed May 2020–January 2021. The changes in breast cancer incidence across the pandemic did not vary by demographic factors. Use of pre-operative systemic therapy across the pandemic varied by geographic region, but not by area socioeconomic deprivation or race/ethnicity. In this US-insured population, the dramatic changes in breast cancer incidence and the use of pre-operative systemic therapy experienced in the first 2 months of the pandemic did not persist, although a modest change in the initial management of breast cancer continued. 

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Breast cancer diagnosis and treatment during the COVID-19 pandemic in a nationwide, insured population

Physician treatment preferences for early stage, estrogen positive breast cancer (ER + BC) patients were evaluated during the initial surge of the COVID-19 pandemic in the US when neoadjuvant endocrine therapy (NET) was recommended to allow safe deferral of surgery. A validated electronic survey was administered May–June, 2020 to US medical oncologists (MO), radiation oncologists (RO), and surgeons (SO) involved in clinical trials organizations. Questions on NET use included practice patterns for locoregional management following NET. 114 Physicians from 29 states completed the survey—42 (37%) MO, 14 (12%) RO, and 58 (51%) SO. Before COVID-19, most used NET ‘rarely’ (49/107, 46%) or ‘sometimes’ (36, 33%) for ER + BC. 46% would delay surgery 2 months without NET. The preferred NET regimen was tamoxifen for premenopausal and aromatase inhibitor for postmenopausal women. 53% planned short term NET until surgery could proceed. Most recommended omitting axillary lymph node dissection (ALND) for one micrometastatic node after 1, 2, or 3 months of NET (1 month, N = 56/93, 60%; 2 months, N = 54/92, 59%; 3 months, N = 48/90, 53%). With longer duration of NET, omission of ALND decreased, regardless of years in practice, percent of practice in BC, practice type, participation in multidisciplinary tumor board, or number of regional COVID-19 cases. More physicians preferred NET for ER + BC during the pandemic, compared with pre-pandemic times. As the duration of NET extended, more providers favored ALND in low volume metastatic axillary disease. The Covid-19 pandemic affected practice of ER + BC; it remains to be seen how this may impact outcomes.

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Joey Bazan

Papers

Neoadjuvant endocrine therapy use in early stage breast cancer during the covid-19 pandemic.