Endothelial dysfunction in breast cancer survivors on aromatase inhibitors: changes over time.

Background: Breast cancer is estimated to comprise about 290,560 new cases in 2022. Aromatase inhibitors (AIs) are recommended as adjuvant treatment for estrogen-receptor positive (ER+) breast carcinoma in postmenopausal women, which includes approximately two-thirds of all women with breast cancer. AIs inhibit the peripheral conversion of androgens to estrogen by deactivation of the aromatase enzyme, leading to a reduction in serum estrogen level in postmenopausal women with ER+ breast carcinoma.

Endothelial Dysfunction in Breast Cancer Survivors on Aromatase Inhibitors: Changes over Time.

Background: Aromatase inhibitors (AIs) are recommended as adjuvant treatment for estrogen-receptor positive breast carcinoma in postmenopausal women. Studies demonstrate mixed results as to the impact of AIs on cardiovascular (CV) events and overall survival. With the increasing number of pre- and postmenopausal women on AIs for five to ten years, understanding the long-term impact of AIs on blood vessels and CV risk in cancer survivors is vital.

Lymphadenopathy after the third Covid-19 vaccine.

Axillary lymphadenopathy ipsilateral to the vaccination site has been clinically and radiologically reported after administration of COVID-19 vaccines. This can be an important diagnostic dilemma, particularly in cancer patients who are being staged or re-staged, as this benign entity may mimic metastasis, cause unnecessary biopsies and changes in therapy. Here we present a breast cancer patient and a patient with squamous cell carcinoma of the head and neck, who had already received the first two doses of mRNA type COVID-19 vaccines before, now presenting with new hypermetabolic reactive lymphadenopathy on FDG PET/CT after the third booster dose.

A Neoadjuvant Chemotherapy Trial for Early Breast Cancer is Impacted by COVID-19: Addressing Vaccination and Cancer Trials Through Education, Equity, and Outcomes.

While COVID-19 vaccine distribution has addressed vulnerabilities related to age and comorbidities, there is a need to ensure vaccination of patients with cancer receiving experimental and routine treatment, where interruption of treatment by infection is likely to result in inferior outcomes. Among patients with cancer, those undergoing neoadjuvant chemotherapy (NAC) or adjuvant chemotherapy (Adj chemo) for early breast cancer (EBC) are at particularly high risk for inferior outcomes, in part, because optimal timing of chemotherapy is essential for promoting distant disease-free survival. COVID-19 data from the ongoing multicenter I-SPY 2 trial of NAC for EBC provides a window into the magnitude of the problem of treatment interruption, not only for the trial itself but also for routine Adj chemo.

Sapanisertib Plus Exemestane or Fulvestrant in Women with Hormone Receptor-Positive/HER2-Negative Advanced or Metastatic Breast Cancer.

Purpose: This open-label, multicenter, phase IB/II study evaluated sapanisertib, a dual inhibitor of mTOR kinase complexes 1/2, plus exemestane or fulvestrant in postmenopausal women with hormone receptor-positive (HR)/HER2-negative (HER2) advanced/metastatic breast cancer.

Patients And Methods: Eligible patients had previously progressed on everolimus with exemestane/fulvestrant and received ≤3 (phase IB) or ≤1 (phase II) prior chemotherapy regimens. Patients received sapanisertib 3 to 5 mg every day (phase IB), or 4 mg every day (phase II) with exemestane 25 mg every day or fulvestrant 500 mg monthly in 28-day cycles.

Recent advances in neoadjuvant therapy for breast cancer.

Neoadjuvant trials for early breast cancer have accelerated the identification of novel active agents, enabling streamlined conduct of registration trials with fewer subjects. Measurement of neoadjuvant drug effects has also enabled the identification of patients with high risk of distant recurrence and has justified development of additional adjuvant approaches to improve outcomes. Neoadjuvant evaluation of new drugs was significantly improved by the introduction of pathologic complete response (pCR) rate as a quantitative surrogate endpoint for distant disease-free survival (DDFS) and event free survival (EFS).

Erratum: Author Correction: Surgical Standards for Management of the Axilla in Breast Cancer Clinical Trials with Pathological Complete Response Endpoint.

[This corrects the article DOI: 10.1038/s41523-018-0074-6.].

Surgical Standards for Management of the Axilla in Breast Cancer Clinical Trials with Pathological Complete Response Endpoint.

Advances in the surgical management of the axilla in patients treated with neoadjuvant chemotherapy, especially those with node positive disease at diagnosis, have led to changes in practice and more judicious use of axillary lymph node dissection that may minimize morbidity from surgery. However, there is still significant confusion about how to optimally manage the axilla, resulting in variation among practices. From the viewpoint of drug development, assessment of response to neoadjuvant chemotherapy remains paramount and appropriate assessment of residual disease-the primary endpoint of many drug therapy trials in the neoadjuvant setting-is critical.

Targeting cytochrome P450-dependent cancer cell mitochondria: cancer associated CYPs and where to find them.

While cytochrome P450 (CYP)-mediated biosynthesis of arachidonic acid (AA) epoxides promotes tumor growth by driving angiogenesis, cancer cell intrinsic functions of CYPs are less understood. CYP-derived AA epoxides, called epoxyeicosatrienoic acids (EETs), also promote the growth of tumor epithelia. In cancer cells, CYP AA epoxygenase enzymes are associated with STAT3 and mTOR signaling, but also localize in mitochondria, where they promote the electron transport chain (ETC).

Heme Binding Biguanides Target Cytochrome P450-Dependent Cancer Cell Mitochondria.

The mechanisms by which cancer cell-intrinsic CYP monooxygenases promote tumor progression are largely unknown. CYP3A4 was unexpectedly associated with breast cancer mitochondria and synthesized arachidonic acid (AA)-derived epoxyeicosatrienoic acids (EETs), which promoted the electron transport chain/respiration and inhibited AMPKα. CYP3A4 knockdown activated AMPKα, promoted autophagy, and prevented mammary tumor formation.

Prolonged survival in patients with breast cancer and a history of brain metastases: results of a preplanned subgroup analysis from the randomized phase III BEACON trial.

Purpose: Conventional chemotherapy has limited activity in patients with breast cancer and brain metastases (BCBM). Etirinotecan pegol (EP), a novel long-acting topoisomerase-1 inhibitor, was designed using advanced polymer technology to preferentially accumulate in tumor tissue including brain metastases, providing sustained cytotoxic SN38 levels.

Methods: The phase 3 BEACON trial enrolled 852 women with heavily pretreated locally recurrent or metastatic breast cancer between 2011 and 2013.

Health-related quality of life in patients with locally recurrent or metastatic breast cancer treated with etirinotecan pegol versus treatment of physician's choice: Results from the randomised phase III BEACON trial.

Background: Health-related quality of life (HRQoL) enhances understanding of treatment effects that impact clinical decision-making. Although the primary end-point was not achieved, the BEACON (BrEAst Cancer Outcomes with NKTR-102) trial established etirinotecan pegol, a long-acting topoisomerase-1 (TOP1) inhibitor, as a promising therapeutic for patients with advanced/metastatic breast cancer (MBC) achieving clinically meaningful benefits in median overall survival (OS) for patients with stable brain metastases, with liver metastases or ≥ 2 sites of metastatic disease compared to treatment of physician's choice (TPC). Reported herein are the findings from the preplanned secondary end-point of HRQoL.

Etirinotecan pegol (NKTR-102) versus treatment of physician's choice in women with advanced breast cancer previously treated with an anthracycline, a taxane, and capecitabine (BEACON): a randomised, open-label, multicentre, phase 3 trial.

Background: New options are needed for patients with heavily pretreated breast cancer. Etirinotecan pegol is a long-acting topoisomerase-I inhibitor that prolongs exposure to, but reduces the toxicity of, SN38 (the active metabolite of irinotecan). We assessed whether etirinotecan pegol is superior to currently available treatments for patients with previously treated, locally recurrent or metastatic breast cancer.

Metformin Treatment for the Prevention and/or Treatment of Breast/Mammary Tumorigenesis.

There is increasing interest in metformin's effects on the development, treatment and/or progression of breast cancer. This emerges from observational studies that diabetic women treated with metformin in comparison to other antidiabetic compounds had lower breast cancer incidence and/or mortality rates. The mechanism of action is considered to be activation of hepatic AMPK resulting in reduced gluconeogenesis.

CYP1A1 regulates breast cancer proliferation and survival.

Cytochrome P450-1A1 (CYP1A1) is an extrahepatic phase I metabolizing enzyme whose expression is suppressed under physiologic conditions but can be induced by substrates via the aryl hydrocarbon receptor (AhR). Recent studies have shown that the majority of breast cancer tumors constitutively express CYP1A1. These findings led us to test the hypothesis that CYP1A1 promotes breast cancer progression by evaluating the effects of CYP1A1 knockdown on the proliferation and survival of the MCF7 and MDA-MB-231 lines.

Should diabetic women with breast cancer have their own intervention studies?

This commentary on 'Calorie restriction and rapamycin inhibit MMTV-Wnt-1 mammary tumor growth in a mouse model of postmenopausal obesity' by Nogueira et al., published in this issue of Endocrine-Related Cancer, addresses the challenges of translating diet, exercise, and pharmacologic trials in diabetic mouse mammary tumor models to human studies. We propose that trials specifically designed to test such interventions in diabetic women with breast cancer would be valuable and informative.

CYP3A4 mediates growth of estrogen receptor-positive breast cancer cells in part by inducing nuclear translocation of phospho-Stat3 through biosynthesis of (±)-14,15-epoxyeicosatrienoic acid (EET).

CYP3A4 expression in breast cancer correlates with decreased overall survival, but the mechanisms are unknown. Cytochrome P450 gene profiling by RNAi silencing demonstrates that CYP3A or 2C8 gene expression is specifically required for growth of the breast cancer lines MCF7, T47D, and MDA-MB-231. CYP3A4 silencing blocks the cell cycle at the G(2)/M checkpoint and induces apoptosis in the MCF7 line, thereby inhibiting anchorage-dependent growth and survival.

The human immunodeficiency virus protease inhibitor ritonavir inhibits lung cancer cells, in part, by inhibition of survivin.

Introduction: Ritonavir is a potential therapeutic agent in lung cancer, but its targets in lung adenocarcinoma are unknown, as are candidate biomarkers for its activity.

Methods: RNAi was used to identify genes whose expression affects ritonavir sensitivity. Synergy between ritonavir, gemcitabine, and cisplatin was tested by isobologram analysis.

Prediction of postoperative recurrence-free survival in non-small cell lung cancer by using an internationally validated gene expression model.

Purpose: This study was performed to discover prognostic genomic markers associated with postoperative outcome of stage I to III non-small cell lung cancer (NSCLC) that are reproducible between geographically distant and demographically distinct patient populations.

Experimental Design: American patients (n = 27) were stratified on the basis of recurrence and microarray profiling of their tumors was performed to derive a training set of 44 genes. A larger Korean patient validation cohort (n = 138) was also stratified by recurrence and screened for these genes.

Anastrozole Use in Early Stage Breast Cancer of Post-Menopausal Women.

The majority of breast cancers express the estrogen receptor and depend on estradiol (E2) for their growth. Hormonal therapy aims at depriving estrogen signaling either by using selective estrogen receptor modulators (SERM)-that interfere with the binding of E2 to its receptor (ER)-or aromatase inhibitors (AI)-that block the aromatase-dependent synthesis of E2. While SERMs are recommended for both pre- and post-menopausal patients, AIs are indicated only for post-menopausal patients.

Gene silencing for epidermal growth factor receptor variant III induces cell-specific cytotoxicity.

Epidermal growth factor receptor variant III (EGFRvIII) is a constitutively active mutant form of EGFR that is expressed in 40% to 50% of gliomas and several other malignancies. Here, we describe the therapeutic effects of silencing EGFRvIII on glioma cell lines in vitro and in vivo. A small interfering RNA molecule against EGFRvIII was introduced into EGFRvIII-expressing glioma cells (U87Delta) by electroporation resulting in complete inhibition of expression of EGFRvIII as early as 48 h post-treatment.