Trastuzumab/pertuzumab combination therapy stimulates antitumor responses through complement-dependent cytotoxicity and phagocytosis.

Two HER2-specific mAbs, trastuzumab and pertuzumab (T+P), combined with chemotherapy comprise standard-of-care treatment for advanced HER2+ breast cancers (BC). While this antibody combination is highly effective, its synergistic mechanism-of-action (MOA) remains incompletely understood. Past studies have suggested that the synergy underlying this combination occurs through the different mechanisms elicited by these antibodies, with pertuzumab suppressing HER2 heterodimerization and trastuzumab inducing antitumor immunity. However, in vivo evidence for this synergy is lacking. In this study, we found that the therapeutic efficacy elicited by their combination occurs through their joint ability to activate the classical complement pathway, resulting in both complement-dependent cytotoxicity and complement-dependent cellular phagocytosis of HER2+ tumors. We also demonstrate that tumor C1q expression is positively associated with survival outcome in HER2+ BC patients and that complement regulators CD55 and CD59 were inversely correlated with outcome, suggesting the clinical importance of complement activity. Accordingly, inhibition of C1q in mice abolished the synergistic therapeutic activity of T+P therapy, whereas knockdown of CD55 and CD59 expression enhanced T+P efficacy. In summary, our study identifies classical complement activation as a significant antitumor MOA for T+P therapy that may be functionally enhanced to potentially augment clinical therapeutic efficacy.

Exploratory study of a screening measure for polycystic ovarian syndrome, quality of life assessment, and neuropsychological evaluation.

BACKGROUND: The universally adopted 2018 PCOS medical diagnostic and treatment guidelines for Polycystic Ovarian Syndrome (PCOS) cites the need for a brief screening measure that can be easily administered in the clinical care setting. We evaluate a 12-item questionnaire emphasizing the medical symptoms of PCOS with a group of women with PCOS as well as comparison samples of college women not diagnosed with PCOS. METHOD: Of 120 undergraduate psychology women 18 to 41 years of age, 86 screened negative on a 12-item PCOS symptoms inventory. They were compared to a group of PCOS patients diagnosed medically in a manner consistent with the Teede et al. (2018) evidence-based diagnostic guidelines. The screen-positive, screen-negative, and PCOS-confirmed groups were compared on the PCOS Quality-of-Life (QoL) questionnaire, Zung Self-Rating Depression Scale (ZDS), Spielberg State-Trait Anxiety Inventory (STAI), Fatigue Symptom Inventory (FSI), Spiritual well-being and Spiritual Beliefs Inventories, the computerized Automated Neuropsychological Assessment Metric (ANAM) battery, and an experimental tachistoscopic Bilateral Perceptual Asymmetries Letter and Dots Matching Bilateral Field Advantage (BFA) test (to evaluate the effects of early brain androgenization possible from PCOS). For each questionnaire and neuropsychological performance principal outcome, the Linear Mixed Effects (LME) model was employed to evaluate the predictive significance of demographic characteristics and group membership (confirmed cases, screen negative and screen positive cases) for these outcomes. RESULTS: The PCOS-confirmed women scored more poorly than the screen-negative (reference) and screen-positive groups on all the measures of physical, emotional, social, and spiritual well-being measures. On the ANAM neuropsychological battery, PCOS-confirmed women did more poorly on Sternberg Memory and Stimulus Response throughput measures. They also had slower correct response speed for both the unilateral and bilateral dot- and letter-matching tachistoscopic stimulus presentations. However, the bilateral field advantage throughput performance ratio did not differ among groups, which is a global measure of bilateral versus unilateral brain/behavior asymmetries. CONCLUSION: PCOS screening can be a feasible and important part of women's healthcare. PCOS-confirmed women should receive not only the medical standard of care from the 2018 guidelines, but also comprehensive psychosocial and neurocognitive support to enhance their quality of life.