OptimICE-RD: sacituzumab govitecan + pembrolizumab vs pembrolizumab (± capecitabine) for residual triple-negative breast cancer.

Patients with early-stage triple-negative breast cancer (TNBC) with residual invasive disease after neoadjuvant therapy have a high risk of recurrence even with neoadjuvant and adjuvant treatment with pembrolizumab. Sacituzumab govitecan, a Trop-2-directed antibody-drug conjugate with a topoisomerase I inhibitor payload, improved progression-free survival (PFS) and overall survival (OS) versus chemotherapy in patients with pre-treated metastatic TNBC. Moreover, preclinical data suggest that topoisomerase I inhibitors may enhance the effects of immune checkpoint inhibitors through activation of the cGAS-STING pathway. Here we describe the international randomized phase III AFT-65/ASCENT-05/OptimICE-RD trial, which evaluates the efficacy and safety of sacituzumab govitecan plus pembrolizumab versus treatment of physician's choice (pembrolizumab ± capecitabine) among patients with early-stage TNBC with residual invasive disease after neoadjuvant therapy.Clinical Trial Registration: NCT05633654 (ClinicalTrials.gov)Other Study ID Number(s): Gilead Study ID: GS-US-595-6184Registration date: 1 December 2022Study start date: 12 December 2022Recruitment status: Recruiting.

AFT-65/ASCENT-05/OptimICE-RD is an ongoing clinical trial that is testing a new treatment combination for patients with stage II or III triple-negative breast cancer (TNBC). Stage II­III means the cancer is confined to the breast and/or nearby lymph nodes and can be surgically removed. However, there remains a risk that the cancer could recur after surgery. To reduce this risk, patients with stage II­III TNBC receive anti-cancer medication before and after surgery. For some patients, receipt of anti-cancer medication before surgery produces a pathologic complete response (pCR), meaning there is no observable cancer left behind at surgery. Patients with a pCR have a lower risk of recurrence than patients with residual disease.The AFT-65/ASCENT-05/OptimICE-RD trial includes people with stage II-III TNBC who have residual cancer after completing their course of pre-surgery anti-cancer medication. All participants have any remaining cancer in their breast and/or lymph nodes removed surgically, after which they are randomly assigned to receive one of two treatments. The experimental therapy consists of pembrolizumab along with a medication called sacituzumab govitecan, which kills cancer cells directly and may strengthen the anti-cancer immune response. Pembrolizumab strengthens the anti-cancer immune response, so the hypothesis of this trial is that the two medications will be more effective together. The control therapy consists of pembrolizumab, alone or in combination with a chemotherapy medication called capecitabine, which is the current standard of care. To study the effectiveness of each treatment, the researchers are following up with all participants to learn if and when their breast cancer returns.

Obese Breast Cancer Patients and Survivors: Management Considerations.

Excess body weight is a significant risk factor for many cancers, especially breast cancer. Patients with breast cancer or those with a history of the disease who are overweight or obese have an increased risk of therapy-related morbidity, recurrence, and breast cancer-related mortality. Obesity may also affect quality-of-life factors for survivors, including sexual dysfunction, neuropathy, cardiotoxicity, chronic fatigue, and lymphedema. Most cancer guidelines recommend that breast cancer survivors who are overweight or obese lose weight and that those with a normal body mass index (BMI) maintain a stable body weight. The cornerstone of interventions to treat or prevent obesity is lifestyle modification with diet and exercise; however, integrating these things into clinical practice is challenging. This article will present feasible weight loss interventions, and will discuss practical implications of ongoing chemotherapy and endocrine therapy with regard to weight gain, and the impact of obesity on therapy-related conditions during breast cancer survivorship.

Management of Metastatic HER2-Positive Breast Cancer: Where Are We and Where Do We Go From Here?

Human epidermal growth factor receptor 2 (HER2)/neu-positive breast cancer has changed from being an aggressive disease with a poor prognosis to a disease that is highly treatable, with prolonged survival possible even in patients with metastatic disease. A better understanding of HER2 biology has led to the development of powerful targeted therapies, and four drugs are already approved by the US Food and Drug Administration for treatment in the metastatic setting (trastuzumab, pertuzumab, lapatinib, and trastuzumab emtansine). Optimizing how these drugs are delivered and in what sequence is an important part of modern management of HER2-positive breast cancer. However, while the prognosis has improved, metastatic disease is still not curable; newer, better drugs are needed. This review will summarize the current standard of care; key issues that arise when treating patients with HER2-positive disease; and developments in novel therapeutics, including small-molecule inhibitors, nanoparticles, immunotherapy, and agents targeting resistance pathways.

The Role of Ovarian Suppression in Premenopausal Women With Hormone Receptor-Positive Early-Stage Breast Cancer.

The optimal adjuvant endocrine therapy in premenopausal women with early-stage breast cancer is yet to be elucidated. Studies have demonstrated that women who experience cessation of ovarian function after chemotherapy (chemotherapy-induced amenorrhea) may experience improved survival. These findings, however, have not been replicated when pharmacologic or surgical interventions have been used to stop ovarian function (eg, gonadotropin-releasing hormone agonists, oophorectomy, or ovarian irradiation) in combination with an endocrine agent such as tamoxifen or an aromatase inhibitor. Recent large phase III clinical trials, including the Austrian Breast and Colorectal Cancer Study Group trial (ABCSG-12), Suppression of Ovarian Function Trial (SOFT), and Tamoxifen and Exemestane Trial (TEXT), did not demonstrate an improvement in disease-free survival with ovarian suppression in the overall population. However, subgroup analyses suggest that women at high risk for recurrence, including very young women or those who have received chemotherapy, may benefit from the addition of ovarian suppression. Still, toxicity and adverse effects on patient-reported outcomes were more frequent in patients who received ovarian suppression; these included more menopausal and sexual dysfunction symptoms, diabetes, hypertension, and osteoporosis. This review will summarize the experience with ovarian suppression in the adjuvant setting for the treatment of premenopausal early-stage breast cancer and offer recommendations for clinical management.

Neoadjuvant Therapy for Early-Stage Breast Cancer: Current Practice, Controversies, and Future Directions.

Research in the fields of surgical, medical, and radiation oncology has changed the landscape of neoadjuvant therapy in breast cancer, yet many areas of controversy still exist. When considering whether a patient is a candidate for neoadjuvant therapy, ideally the initial assessment should be multidisciplinary in nature and should include clinical, radiographic, and pathologic evaluation. Optimization of systemic therapy is dependent upon identifying the patient's breast cancer subtype; the best approach may include targeted agents, as well as the determination of eligibility for enrollment into clinical trials that incorporate novel therapeutics or predictive biomarkers. This article will review a variety of surgical and radiation-based strategies for management of early-stage breast cancer, including surgical options involving the breast and axilla, and the role of radiation based on response to systemic therapy. Key areas of controversy include the ideal systemic treatment for different breast cancer subtypes, the surgical and radiotherapeutic approaches for management of the axilla, and the role of pathologic response rates as a surrogate for survival in drug development.

Aggressive estrogen-receptor-positive breast cancer arising in patients with elevated body mass index.

BACKGROUND: Obese women with estrogen receptor (ER)-positive breast cancer may experience worse disease-free and overall survival. We hypothesize that this observation is due to intrinsically aggressive disease and that obesity will be associated with higher histologic grade and Ki67. METHODS: A sequential cohort of women with breast cancer diagnosed over 2 years was assembled from institutional tumor registries. Patient and tumor characteristics were abstracted from medical records; those with non-invasive tumors, or lacking body mass index (BMI), Ki67 or histologic grade data, were excluded. Univariate and multivariate analysis was performed to investigate the relationship between markers of aggressive disease (grade and Ki67) and multiple variables associated with obesity. A subgroup analysis was performed to investigate further whether ER and menopausal status influenced associations between BMI and aggressive phenotypes. RESULTS: Of the 1007 patients initially identified, 668 (68 %) met the eligibility criteria. In univariate analysis, histologic grade and Ki67 were strongly associated with increased BMI, younger age, and African-American race, but less so with diabetes, hypertension, and hyperlipidemia. Multivariate analysis confirmed that higher histologic grade was associated with increased BMI (p = 0.02), and that increased Ki67 was associated with younger age (p = 0.0003) and African-American race (p = 0.002). Additional analysis found that the association between increased BMI and higher-grade tumors was particularly significant in premenopausal women with ER-positive disease. CONCLUSION: This study concludes that increased BMI is associated with aggressive-phenotype breast cancer and may be particularly relevant to ER-positive breast cancer developing in premenopausal African-American women.

Patient-reported Outcomes of Patients With Breast Cancer During the COVID-19 Outbreak in the Epicenter of China: A Cross-sectional Survey Study.

INTRODUCTION: We aimed to analyze the psychological status in patients with breast cancer (BC) in the epicenter of the coronavirus disease 2019 (COVID-19) pandemic. PATIENTS AND METHODS: A total of 658 individuals were recruited from multiple BC centers in Hubei Province. Online questionnaires were conducted, and these included demographic information, clinical features, and 4 patient-reported outcome scales (Generalized Anxiety Disorder Questionnaire [GAD-7], Patient Health Questionnaire [PHQ-9], Insomnia Severity Index [ISI], and Impact of Events Scale-Revised [IES-R]). Multivariable logistic regression analysis was designed to identify potential factors on mental health outcomes. RESULTS: Questionnaires were collected from February 16, 2020 to February 19, 2020, the peak time point of the COVID-19 outbreak in China. Of patients with BC, 46.2% had to modify planned necessary anti-cancer treatment during the outbreak. Severe anxiety and severe depression were reported by 8.9% and 9.3% of patients, respectively. Severe distress and insomnia were reported by 20.8% and 4.0% of patients, respectively. Multivariable logistic regression analysis demonstrated poor general condition, shorter duration after BC diagnosis, aggressive BC molecular subtypes, and close contact with patients with COVID-19 as independent factors associated with anxiety. Poor general condition and central venous catheter flushing delay were factors that were independently associated with depression. In terms of insomnia, poor generation condition was the only associated independent factor. Poor physical condition and treatment discontinuation were underlying risk factors for distress based on multivariable analysis. CONCLUSION: High rates of anxiety, depression, distress, and insomnia were observed in patients with BC during the COVID-19 outbreak. Special attention should be paid to the psychological status of patients with BC, especially those with poor general condition, treatment discontinuation, aggressive molecular subtypes, and metastatic BC.

Manganese Superoxide Dismutase Acetylation and Dysregulation, Due to Loss of SIRT3 Activity, Promote a Luminal B-Like Breast Carcinogenic-Permissive Phenotype.

SIGNIFICANCE: Breast cancer is the most common nondermatologic malignancy among women in the United States, among which endocrine receptor-positive breast cancer accounts for up to 80%. Endocrine receptor-positive breast cancers can be categorized molecularly into luminal A and B subtypes, of which the latter is an aggressive form that is less responsive to endocrine therapy with inferior prognosis. RECENT ADVANCES: Sirtuin, an aging-related gene involved in mitochondrial metabolism, is associated with life span, and more importantly, murine models lacking Sirt3 spontaneously develop tumors that resemble human luminal B breast cancer. Furthermore, these tumors exhibit aberrant manganese superoxide dismutase (MnSOD) acetylation at lysine 68 and lysine 122 and have abnormally high reactive oxygen species (ROS) levels, which have been observed in many types of breast cancer. CRITICAL ISSUES: The mechanism of how luminal B breast cancer develops resistance to endocrine therapy remains unclear. MnSOD, a primary mitochondrial detoxification enzyme, functions by scavenging excessive ROS from the mitochondria and maintaining mitochondrial and cellular homeostasis. Sirt3, a mitochondrial fidelity protein, can regulate the activity of MnSOD through deacetylation. In this study, we discuss a possible mechanism of how loss of SIRT3-guided MnSOD acetylation results in endocrine therapy resistance of human luminal B breast cancer. FUTURE DIRECTIONS: Acetylation of MnSOD and other mitochondrial proteins, due to loss of SIRT3, may explain the connection between ROS and development of luminal B breast cancer and how luminal B breast cancer becomes resistant to endocrine therapy. Antioxid. Redox Signal. 25, 326-336.