Neoadjuvant endocrine therapy in postmenopausal women with HR+/HER2- breast cancer.

INTRODUCTION: While endocrine therapy is the standard-of-care adjuvant treatment for hormone receptor-positive (HR+) breast cancers, there is also extensive evidence for the role of pre-operative (or neoadjuvant) endocrine therapy (NET) in HR+ postmenopausal women. AREAS COVERED: We conducted a thorough review of the published literature, to summarize the evidence to date, including studies of how NET compares to neoadjuvant chemotherapy, which NET agents are preferable, and the optimal duration of NET. We describe the importance of on-treatment assessment of response, the different predictors available (including Ki67, PEPI score, and molecular signatures) and the research opportunities the pre-operative setting offers. We also summarize recent combination trials and discuss how the COVID-19 pandemic led to increases in NET use for safe management of cases with deferred surgery and adjuvant treatments. EXPERT OPINION: NET represents a safe and effective tool for the management of postmenopausal women with HR+/HER2- breast cancer, enabling disease downstaging and a wider range of surgical options. Aromatase inhibitors are the preferred NET, with evidence suggesting that longer regimens might yield optimal results. However, NET remains currently underutilised in many territories and institutions. Further validation of predictors for treatment response and benefit is needed to help standardise and fully exploit the potential of NET in the clinic.

A phase III, randomized, open-label study (CONTACT-02) of cabozantinib plus atezolizumab versus second novel hormone therapy in patients with metastatic castration-resistant prostate cancer.

Cabozantinib inhibits multiple receptor tyrosine kinases, including the TAM kinase family, and may enhance response to immune checkpoint inhibitors. One cohort of the ongoing phase Ib COSMIC-021 study (NCT03170960) evaluating cabozantinib plus the PD-L1 inhibitor atezolizumab in men with metastatic castration-resistant prostate cancer (mCRPC) that has progressed in soft tissue on/after enzalutamide and/or abiraterone treatment for metastatic disease has shown promising efficacy. Here, we describe the rationale and design of a phase III trial of cabozantinib plus atezolizumab versus a second novel hormone therapy (NHT) in patients who have previously received an NHT for mCRPC, metastatic castration-sensitive PC or nonmetastatic CRPC and have measurable visceral disease and/or extrapelvic adenopathy - a population with a significant unmet need for treatment options. Trial Registration Clinical Trial Registration: NCT04446117 (ClinicalTrials.gov) Registered on 24 June 2020.

Delays in operative management of early-stage, estrogen receptor-positive breast cancer during the COVID-19 pandemic: A multi-institutional matched historical cohort study.

BACKGROUND: During the COVID-19 pandemic, guidelines recommended that breast cancer centers delay estrogen receptor-positive breast cancer surgeries with neoadjuvant endocrine therapy. We aimed to evaluate pathologic upstaging of breast cancer patients affected by these guidelines. METHODS: Female patients with stage I/II breast cancer receiving neoadjuvant endocrine therapy were prospectively identified and were matched to a historical cohort of stage I/II estrogen receptor-positive breast cancer patients treated with upfront surgery ≤35 days. Primary outcomes were pathologic T and N upstaging versus clinical staging. RESULTS: After matching, 28 neoadjuvant endocrine therapy and 48 control patients remained. Median age in each group was 65 (P = .68). Most patients (78.6% and 79.2%) had invasive ductal carcinoma with a clinical tumor size of 0.9 cm vs 1.7 cm (P = .056). Time to surgery was 68 days in the neoadjuvant endocrine therapy group and 26.5 days in the control (P < .001). A total of 23 neoadjuvant endocrine therapy patients (82.1%) had the same or lower pT-stage compared with 31 (64.5%) control patients (P = .115). Only 3 (10.7%) neoadjuvant endocrine therapy patients had increased pN-stage vs 14 (29.2%) control patients (P = .063). CONCLUSION: Despite 2.5-times longer delays, patients with early-stage estrogen receptor-positive breast cancer receiving neoadjuvant endocrine therapy did not experience pathologic upstaging during the COVID-19 pandemic. These findings may support the use of neoadjuvant endocrine therapy in similar patients if delays to surgery are projected.

Bridging Endocrine Therapy for HR+/HER2- Resectable Breast Cancer: Is it Safe?

BACKGROUND: The COVID-19 pandemic has required new treatment paradigms to limit exposures and optimize hospital resources, including the use of neoadjuvant endocrine therapy (NAET) as bridging therapy for HR+/HER2-invasive tumors and DCIS. While this approach has been used in locally advanced disease, it is unclear how it may affect outcomes in resectable HR+/HER2- tumors. METHODS: Women ≥18 years diagnosed with in situ (Tis) or non-metastatic HR+/HER2- breast cancer from March-May 2019 and 2020 were included. Fisher's exact test and two-sample t test were used to compare baseline characteristics and surgical outcomes between strata. Sub-analysis was performed between patients who received primary surgery vs a bridging NAET approach. RESULTS: Despite similar clinical characteristics, patients in 2019 were more likely to have a surgery-first approach (75% vs 42%, P-value = .0007), receive surgery sooner (22 vs 29 days, P-value < .001), and within 60 days from diagnosis date (100% vs 85%, P-value = .0301). Neoadjuvant endocrine therapy was a more prevalent approach in 2020 (48% vs 7%, P-value < .0001). Rates of clinical to pathologic up-staging remained consistent across primary surgery vs bridging NAET subgroups (P-value = .9253). DISCUSSION: Pandemic-driven treatment protocols provide a unique opportunity to assess the utility of bridging endocrine therapy for resectable HR+/HER2- tumors. Differences in clinical and pathologic staging were similar across groups and did not appear to be affected by receipt of NAET. Our limited cohort demonstrates this strategic therapeutic avenue can optimize health care utilization and may be a reasonable approach when delaying surgery is preferred.

Glycemic Profile of Intravenous Dexamethasone-Induced Hyperglycemia Using Continuous Glucose Monitoring.

BACKGROUND Intravenous (IV) dexamethasone is widely used in critical illness, chemotherapy, or severe COVID-19. Although glucocorticoid-induced hyperglycemia (GCIH) is well-known, there is no report describing the glycemic profile following a single dose of IV dexamethasone as captured on continuous glucose monitoring (CGM) in a patient with diabetes treated with insulin. CASE REPORT A 70-year-old woman with diabetes and pancreatic adenocarcinoma was treated with chemotherapy containing dexamethasone every other week. CGM data of 23 cycles revealed a reproducible triphasic glycemic pattern consisting of a constant hyperglycemia period, followed by a transient improvement, and ending with another hyperglycemic plateau. Given this recurrent pattern, basal insulin and correction insulin were adjusted with subsequent GCIH attenuation. CONCLUSIONS This is the first report of CGM glycemic profile following recurring doses of IV dexamethasone in a patient with diabetes treated with basal-bolus insulin. The understanding of triphasic glycemic pattern allows optimal glycemic management.

Cardiovascular Toxicities of Androgen Deprivation Therapy.

OPINION STATEMENT: Prostate cancer is the second leading cause of cancer death in men, and cardiovascular disease is the number one cause of death in patients with prostate cancer. Androgen deprivation therapy, the cornerstone of prostate cancer treatment, has been associated with adverse cardiovascular events. Emerging data supports decreased cardiovascular risk of gonadotropin releasing hormone (GnRH) antagonists compared to agonists. Ongoing clinical trials are assessing the relative safety of different modalities of androgen deprivation therapy. Racial disparities in cardiovascular outcomes in prostate cancer patients are starting to be explored. An intriguing inquiry connects androgen deprivation therapy with reduced risk of COVID-19 infection susceptibility and severity. Recognition of the cardiotoxicity of androgen deprivation therapy and aggressive risk factor modification are crucial for optimal patient care.

Breast cancer patients' insurance status and residence zip code correlate with early discontinuation of endocrine therapy: An analysis of the ECOG-ACRIN TAILORx trial.

BACKGROUND: Early discontinuation is a substantial barrier to the delivery of endocrine therapies (ETs) and may influence recurrence and survival. The authors investigated the association between early discontinuation of ET and social determinants of health, including insurance coverage and the neighborhood deprivation index (NDI), which was measured on the basis of patients' zip codes, in breast cancer. METHODS: In this retrospective analysis of a prospective randomized clinical trial (Trial Assigning Individualized Options for Treatment), women with hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer who started ET within a year of study entry were included. Early discontinuation was calculated as stopping ET within 4 years of its start for reasons other than distant recurrence or death via Kaplan-Meier estimates. A Cox proportional hazards joint model was used to analyze the association between early discontinuation of ET and factors such as the study-entry insurance and NDI, with adjustments made for other variables. RESULTS: Of the included 9475 women (mean age, 55.6 years; White race, 84%), 58.0% had private insurance, whereas 11.7% had Medicare, 5.8% had Medicaid, 3.8% were self-pay, and 19.1% were treated at international sites. The early discontinuation rate was 12.3%. Compared with those with private insurance, patients with Medicaid (hazard ratio [HR], 1.53; 95% confidence interval [CI], 1.23-1.92) and self-pay patients (HR, 1.65; 95% CI, 1.25-2.17) had higher early discontinuation. Participants with a first-quartile NDI (highest deprivation) had a higher probability of discontinuation than those with a fourth-quartile NDI (lowest deprivation; HR, 1.34; 95% CI, 1.11-1.62). CONCLUSIONS: Patients' insurance and zip code at study entry play roles in adherence to ET, with uninsured and underinsured patients having a high rate of treatment nonadherence. Early identification of patients at risk may improve adherence to therapy. LAY SUMMARY: In this retrospective analysis of 9475 women with breast cancer participating in a clinical trial (Trial Assigning Individualized Options for Treatment), Medicaid and self-pay patients (compared with those with private insurance) and those in the highest quartile of neighborhood deprivation scores (compared with those in the lowest quartile) had a higher probability of early discontinuation of endocrine therapy. These social determinants of health assume larger importance with the expected increase in unemployment rates and loss of insurance coverage in the aftermath of the coronavirus disease 2019 pandemic. Early identification of patients at risk and enrollment in insurance optimization programs may improve the persistence of therapy.

Risk-adapted adjuvant therapy of luminal early breast cancer in 2020.

PURPOSE OF REVIEW: The present review summarizes recent original publications addressing the topic of risk-adapted adjuvant therapy in early breast cancer (EBC). As neoadjuvant therapy has become a standard for triple negative and HER2+ EBC, it focusses on luminal EBC. RECENT FINDINGS: Gene expression assays have become standard of care in luminal EBC, at least for patients with node negative disease. Two prospective randomized clinical trials, TAILORx (Oncotype DX) and MINDACT (MammaPrint) have presented additional analyses underlining the clinical utility of the tests. In times of COVID-19, immunohistochemically determined ER, PR, and Ki67 and early Ki67 response to endocrine therapy can be used to safely allocate patients for preoperative endocrine therapy and delay surgeries if resources are scarce. In patients with luminal high-risk disease, adding a CDK 4/6 inhibitor (abemaciclib) improves patient outcome already after short-term follow-up. SUMMARY: Determination of recurrence risk will remain important in luminal EBC for optimal therapy decisions. In the future, risk-adapted treatment concepts will include decision making for chemotherapy but also for endocrine-based approaches.

Estrogen and Androgen Receptor Inhibitors: Unexpected Allies in the Fight Against COVID-19.

TRANSLATIONAL RELEVANCE: No prophylactic treatments for COVID-19 have been clearly proven and found. In this pandemic context, cancer patients constitute a particularly fragile population that would benefit the best from such treatments, a present unmet need. TMPRSS2 is essential for COVID-19 replication cycle and it is under androgen control. Estrogen and androgen receptor dependent cues converge on TMPRSS2 regulation through different mechanisms of action that can be blocked by the use of hormonal therapies. We believe that there is enough body of evidence to foresee a prophylactic use of hormonal therapies against COVID-19 and this hypothesis can be easily tested on cohorts of breast and prostate cancer patients who follow those regimens. In case of pandemic, if the protective effect of hormonal therapies will be proven on cancer patients, the use of specific hormonal therapies could be extended to other oncological groups and to healthy individuals to decrease the overall risk of infection by SARS-CoV-2.Given the COVID-19 coronavirus emergency, a special focus is needed on the impact of this rapidly spreading viral infection on cancer patients. Androgen receptor (AR) signaling in the transmembrane protease serine 2 (TMPRSS2) regulation is emerging as an important determinant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) susceptibility. In our study, we analyzed AR and TMPRSS2 expression in 17,352 normal and 9,556 cancer tissues from public repositories and stratified data according to sex and age. The emerging picture is that some patient groups may be particularly susceptible to SARS-CoV-2 infection and may benefit from antiandrogen- or tamoxifen-based therapies. These findings are relevant to choose proper treatments in order to protect cancer patients from concomitant SARS-CoV-2 contagion and related symptoms and put forward the idea that hormonal therapies could be used as prophylactic agents against COVID-19.

Management of early breast cancer during the COVID-19 pandemic in Brazil.

PURPOSE: The COVID-19 pandemic has impacted early breast cancer (EBC) treatment worldwide. This study analyzed how Brazilian breast specialists are managing EBC. METHODS: An electronic survey was conducted with members of the Brazilian Society of Breast Cancer Specialists (SBM) between April 30 and May 11, 2020. Bivariate analysis was used to describe changes in how specialists managed EBC at the beginning and during the pandemic, according to breast cancer subtype and oncoplastic surgery. RESULTS: The response rate was 34.4% (503/1462 specialists). Most of the respondents (324; 64.4%) lived in a state capital city, were board-certified as breast specialists (395; 78.5%) and either worked in an academic institute or one associated with breast cancer treatment (390; 77.5%). The best response rate was from the southeast of the country (240; 47.7%) followed by the northeast (128; 25.4%). At the beginning of the pandemic, 43% changed their management approach. As the outbreak progressed, this proportion increased to 69.8% (p < 0.001). The southeast of the country (p = 0.005) and the state capital cities (p < 0.001) were associated with changes at the beginning of the pandemic, while being female (p = 0.001) was associated with changes during the pandemic. For hormone receptor-positive tumors with the best prognosis (Ki-67 < 20%), 47.9% and 17.7% of specialists would recommend neoadjuvant endocrine therapy for postmenopausal and premenopausal women, respectively. For tumors with poorer prognosis (Ki-67 > 30%), 34% and 10.9% would recommend it for postmenopausal and premenopausal women, respectively. Menopausal status significantly affected whether the specialists changed their approach (p < 0.00001). For tumors ≥ 1.0 cm, 42.9% of respondents would recommend neoadjuvant systemic therapy for triple-negative tumors and 39.6% for HER2 + tumors. Overall, 63.4% would recommend immediate total breast reconstruction, while only 3.4% would recommend autologous reconstruction. In breast-conserving surgery, 75% would recommend partial breast reconstruction; however, 54.1% would contraindicate mammoplasty. Furthermore, 84.9% of respondents would not recommend prophylactic mastectomy in cases of BRCA mutation. CONCLUSIONS: Important changes occurred in EBC treatment, particularly for hormone receptor-positive tumors, as the outbreak progressed in each region. Systematic monitoring could assure appropriate breast cancer treatment, mitigating the impact of the pandemic.

Sex differences in SARS-CoV-2 infection rates and the potential link to prostate cancer.

The recent outbreak of infections and the pandemic caused by SARS-CoV-2 represent one of the most severe threats to human health in more than a century. Emerging data from the United States and elsewhere suggest that the disease is more severe in men. Knowledge gained, and lessons learned, from studies of the biological interactions and molecular links that may explain the reasons for the greater severity of disease in men, and specifically in the age group at risk for prostate cancer, will lead to better management of COVID-19 in prostate cancer patients. Such information will be indispensable in the current and post-pandemic scenarios.

COVID-19 and the male susceptibility: the role of ACE2, TMPRSS2 and the androgen receptor.

COVID-19 is the pandemic that hit the world starting December 2019. Recent studies and international statistics have shown an increased prevalence, morbidity as well as mortality of this disease in male patients compared to female patients. The aim of this brief communication is to describe the pathophysiology of this sex-discrepancy, based on the infectivity mechanism of the coronavirus including the Angiotensin-Converting Enzyme 2 (ACE2), the Type II transmembrane Serine Protease (TMPRSS2), and the androgen receptor. This could help understand the susceptibility of urological patients, especially those receiving androgen deprivation therapy for prostate cancer, and testosterone replacement therapy.

Breast cancer care during a pandemic: an opportune time for cryoablation?

PURPOSE: Cryoablation is a minimally-invasive percutaneous procedure that is capable of reducing the psychosocial burden of surgical delay while also decreasing the morbidity of breast cancer therapy. The purpose of this editorial is to discuss the potential role of cryoablation for reducing the psychosocial burden of surgical delay during the COVID-19 pandemic by expediting the management of breast cancer while also lessening demand on limited healthcare resources. METHODS: This editorial critiques current expert opinion recommendations that aim to reduce viral transmission and preserve healthcare resources during the COVID-19 pandemic by advocating delay of elective breast cancer surgery. RESULTS: The editorial summarizes the current state of the evidence that supports the selective use of cryoablation as a definite or stopgap measure in the management of breast cancer during the COVID-19 pandemic or when healthcare resources are limited. CONCLUSIONS: As an office-based procedure performed under local anesthesia, cryoablation eliminates the need for operating room personnel and equipment while also reducing the psychosocial impact of delayed breast cancer surgery. By reducing the number of patient and healthcare provider interactions, cryoablation not only decreases the risk of viral transmission but also the need for personal protective devices during resource-limited times.

Changes in breast cancer management during the Corona Virus Disease 19 pandemic: An international survey of the European Breast Cancer Research Association of Surgical Trialists (EUBREAST).

BACKGROUND: Corona Virus Disease 19 (COVID-19) had a worldwide negative impact on healthcare systems, which were not used to coping with such pandemic. Adaptation strategies prioritizing COVID-19 patients included triage of patients and reduction or re-allocation of other services. The aim of our survey was to provide a real time international snapshot of modifications of breast cancer management during the COVID-19 pandemic. METHODS: A survey was developed by a multidisciplinary group on behalf of European Breast Cancer Research Association of Surgical Trialists and distributed via breast cancer societies. One reply per breast unit was requested. RESULTS: In ten days, 377 breast centres from 41 countries completed the questionnaire. RT-PCR testing for SARS-CoV-2 prior to treatment was reported by 44.8% of the institutions. The estimated time interval between diagnosis and treatment initiation increased for about 20% of institutions. Indications for primary systemic therapy were modified in 56% (211/377), with upfront surgery increasing from 39.8% to 50.7% (p < 0.002) and from 33.7% to 42.2% (p < 0.016) in T1cN0 triple-negative and ER-negative/HER2-positive cases, respectively. Sixty-seven percent considered that chemotherapy increases risks for developing COVID-19 complications. Fifty-one percent of the responders reported modifications in chemotherapy protocols. Gene-expression profile used to evaluate the need for adjuvant chemotherapy increased in 18.8%. In luminal-A tumours, a large majority (68%) recommended endocrine treatment to postpone surgery. Postoperative radiation therapy was postponed in 20% of the cases. CONCLUSIONS: Breast cancer management was considerably modified during the COVID-19 pandemic. Our data provide a base to investigate whether these changes impact oncologic outcomes.