Unraveling the clinicopathological and molecular changes induced by neoadjuvant chemotherapy and endocrine therapy in hormone receptor-positive/HER2-low and HER2-0 breast cancer.

BACKGROUND: The characterization and comparison of gene expression and intrinsic subtype (IS) changes induced by neoadjuvant chemotherapy (NACT) and endocrine therapy in hormone receptor-positive (HR+)/human epidermal growth factor receptor 2 (HER2)-low versus HR+/HER2-0 breast cancer (BC) has not been conducted so far. Most evidence on the association of HER2 status with pathologic responses and prognosis in HR+/HER2-negative BC is controversial and restricted to NACT-treated disease. Similarly, a temporal heterogeneity in HER2 status has been described only with NACT. METHODS: We retrospectively recruited a consecutive cohort of 186 patients with stage I-IIIB HR+/HER2-negative BC treated with neoadjuvant therapy (NAT). Available diagnostic biopsies and surgical samples were characterized for main pathological features, PAM50 IS and ROR-P score, and gene expression. Associations with pathologic complete response, residual cancer burden-0/I, event-free survival (EFS) and overall survival (OS) based on HER2 status were assessed. Pre/post pathologic/molecular changes were analyzed in matched samples. RESULTS: The HER2-low (62.9%) and HER2-0 (37.1%) cohorts did not differ significantly in main baseline features, treatments administered, breast-conserving surgery, pathologic complete response and residual cancer burden-0/I rates, EFS, and OS. NAT induced, regardless of HER2 status, a significant reduction of estrogen receptor/progesterone receptor and Ki67 levels, a down-regulation of PAM50 proliferation- and luminal-related genes/signatures, an up-regulation of selected immune genes, and a shift towards less aggressive IS and lower ROR-P. Moreover, 25% of HER2-0 changed to HER2-low and 34% HER2-low became HER2-0. HER2 shifts were significant after NACT (P < 0.001), not neoadjuvant endocrine therapy (P = 0.063), with consistent ERBB2 mRNA level dynamics. HER2 changes were not associated with EFS/OS. CONCLUSIONS: HER2-low and HER2-0 status change after NAT in ∼30% of cases, mostly after NACT. Targeted adjuvant strategies should be investigated accordingly. Molecular downstaging with current chemo/endocrine agents and immunotherapy should not rely on HER2 immunohistochemical levels in HR+/HER2-negative BC. Instead, HER2-low-targeted approaches should be explored to pursue more effective and/or less toxic dimensional downstaging.

Treating genitourinary syndrome of menopause in breast cancer survivors: main challenges and promising strategies.

Many breast cancer survivors (BCS) suffer the consequences of antineoplastic treatments that induce a hypoestrogenic state, leading to chronic climacteric symptoms such as genitourinary syndrome of menopause (GSM), arousing significant alteration in their quality of life. Non-hormonal therapies (NHT) are first-line treatments, safe but with mild efficacy. When facing moderate-severe GSM, the options for BCS are limited: local estrogen therapy, considered the 'gold standard' but with concerns about safety; vaginal androgens and prasterone, which seem to trigger an activation of estrogen and androgen receptors of the vaginal epithelium layers, without activating estrogen receptors on other tissues, being potentially safe but still without strong evidence in favor of BCS; vaginal lasers, which appear to improve vascularization of vaginal mucosa by stimulating the remodeling of the underlying connective tissue, but with contradictory results of efficacy in recent randomized clinical trials; and ospemifene, an oral selective estrogen receptor modulator presenting mild vaginal estrogenic potency and anti-estrogenic effect at the endometrial and breast level, but still not recommended for use in BCS in recent North American Menopause Society guidelines. There is a need for further studies evaluating objectively the efficacy and safety of these promising therapeutic options. On the other hand, sexuality must be seen as a multifactorial issue, where GSM is only part of the problem; evidence shows that sexual counseling improves the quality of life of BCS. Finally, there is a need to limit the underdiagnosis and undertreatment of GSM in BCS; the primary goal of physicians treating BCS regarding this issue has to be the provision of information of what to expect regarding genital and sexual symptoms to BCS and to counsel on early first-line treatments that may help prevent more severe GSM.

Semillas radiactivas y no radiactivas como método de localización quirúrgica de las lesiones mamarias no palpables / Radioactive and non-radioactive seeds as surgical localization method of non-palpable breast lesions

El diagnóstico cada vez más precoz de la enfermedad mamaria y el uso más extendido del tratamiento sistémico primario conlleva en la práctica clínica un creciente número de cirugías de lesiones mamarias no palpables (LMNP).La cirugía conservadora de la mama requiere a menudo la utilización de un procedimiento de localización preoperatorio guiado por imagen, en el cual se coloca un dispositivo en el interior de la lesión a extirpar para guiar al cirujano durante la cirugía. Se trata de pacientes con tumores pequeños, no palpables, detectados en la mamografía de cribado poblacional, casos con significativa reducción de la lesión tras la quimioterapia neoadyuvante e incluso en ocasiones es necesario el marcaje de adenopatías axilares previo al tratamiento sistémico.Durante décadas, la localización con arpón ha sido el estándar para el marcaje preoperatorio en cáncer de mama. Debido al componente externo del arpón, se debe extremar el cuidado de no alterar su posición antes de la cirugía, por lo que se coloca horas antes de la cirugía y conlleva una compleja y limitada flexibilidad de programación quirúrgica.La ecografía intraoperatoria subsana este inconveniente, pero tiene la limitación de que únicamente va a poder realizarse en aquellas LMNP que tienen traducción ecográfica. La técnica Radioguided Ocult Lesión Localization (ROLL), si bien es otra alternativa adoptada por muchas instituciones, no está exenta de complicaciones, entre las que destaca la posibilidad de difusión del radiotrazador hacia el tejido sano.Para solventar estos inconvenientes, más recientemente, se comenzaron a utilizar las semillas radiactivas de 125I. Posteriormente, gracias a los avances tecnológicos, han surgido alternativas de semillas no radiactivas como los reflectores de radar, las semillas magnéticas y los marcadores por radiofrecuencia. Estos dispositivos de localización se pueden colocar días antes de la cirugía

The increasingly early diagnosis of breast disease and the more widespread use of primary systemic therapy leads to an increasing number of surgeries for non-palpable breast lesions (NPL) in clinical practice.Breast-conserving surgery often requires the use of an image-guided preoperative localization procedure, in which a device is placed within the lesion to be removed to guide the surgeon during surgery. These are patients with small, non-palpable tumors detected in the population screening mammogram, cases with significant reduction of the lesion after neoadjuvant chemotherapy and sometimes it is even necessary to mark axillary lymphadenopathies prior to systemic treatment.For decades, wire localization has been the standard for preoperative marking in breast cancer. Due to the external component of this device, extreme care must be taken not to alter its position before surgery, which is why it is placed hours before surgery and entails complex and limited flexibility in surgical programming.Intraoperative ultrasound improves this drawback but has the limitation that it can only be performed in those NPLs that have ultrasound translation. The Radioguided Occult Lesion Localization (ROLL) technique, although it is another alternative adopted by many institutions, is not without complications, among which the possibility of diffusion of the radiotracer into healthy tissue stands out.To overcome these problems, more recently, 125I radioactive seeds began to be used. Subsequently, thanks to technological advances, non-radioactive seed alternatives such as radar reflectors, magnetic seeds and radio frequency markers have emerged. These locating devices can be placed days before surgery, avoiding wire-related problems and complications. They are introduced percutaneously and identified intraoperatively using a detector device.There is no perfect intraoperative localization method for NPL excision, but fortunately, we have multiple techniques

Safety of prasterone in breast cancer survivors treated with aromatase inhibitors: the VIBRA pilot study.

BACKGROUND: Due to safety concerns on estrogen-based treatments for genitourinary syndrome of menopause (GSM) in breast cancer survivors (BCS), new options are appearing, such as androgen-based treatments, which according to proprieties would not be transformed systemically to estrogens in patients receiving aromatase inhibitors (AIs). OBJECTIVE: The aim of this pilot study is to assess the security and efficacy of vaginal prasterone (dehydroepiandrostenedione [DHEA]) in BCS treated with AIs. METHODS: This open, prospective, pilot study included 10 BCS treated with AIs. All participants complained of severe GSM. DHEA was administrated as a vaginal ovule. Participants were instructed to use one ovule every night during the first month, and one ovule every two nights for the entire five remaining months. The patients were requested to attend seriated visits after the beginning of the prasterone treatment to evaluate symptoms, physical improvement and serum estradiol. RESULTS: Mean serum estradiol remained low from 3.4 pg/ml to 4.3 pg/ml (p = 0.9136) after 6 months of follow-up. The visual analog scale of dyspareunia improved from 8.5 to mean values after treatment of 0.4 (p = 0.0178). The Vaginal Health Index (VHI) scale and Female Sexual Function Index improved from 9.75 to 15.8 (p = 0.0277) and from an initial score of 11.2 to 20.6 (p = 0.0277), respectively. Vaginal pH changed from basal 8.1 to final 6.5 (p = 0.0330). CONCLUSION: Symptoms and physical examination regarding sexuality and vaginal health improved significantly, while serum estradiol remained at low levels. Prasterone seems a safe and effective option to treat GSM in BCS receiving AIs.

Radioactive and non-radioactive seeds as surgical localization method of non-palpable breast lesions.

The increasingly early diagnosis of breast disease and the more widespread use of primary systemic therapy leads to an increasing number of surgeries for non-palpable breast lesions (NPL) in clinical practice. Breast-conserving surgery often requires the use of an image-guided preoperative localization procedure, in which a device is placed within the lesion to be removed to guide the surgeon during surgery. These are patients with small, non-palpable tumors detected in the population screening mammogram, cases with significant reduction of the lesion after neoadjuvant chemotherapy and sometimes it is even necessary to mark axillary lymphadenopathies prior to systemic treatment. For decades, wire localization has been the standard for preoperative marking in breast cancer. Due to the external component of this device, extreme care must be taken not to alter its position before surgery, which is why it is placed hours before surgery and entails complex and limited flexibility in surgical programming. Intraoperative ultrasound improves this drawback but has the limitation that it can only be performed in those NPLs that have ultrasound translation. The Radioguided Occult Lesion Localization (ROLL) technique, although it is another alternative adopted by many institutions, is not without complications, among which the possibility of diffusion of the radiotracer into healthy tissue stands out. To overcome these problems, more recently, 125I radioactive seeds began to be used. Subsequently, thanks to technological advances, non-radioactive seed alternatives such as radar reflectors, magnetic seeds and radio frequency markers have emerged. These locating devices can be placed days before surgery, avoiding wire-related problems and complications. They are introduced percutaneously and identified intraoperatively using a detector device. There is no perfect intraoperative localization method for NPL excision, but fortunately, we have multiple techniques with different advantages and disadvantages that must be assessed and adapted to the center's own resources, the type of surgery, and always to the benefit of the patient.

Transvaginal ultrasound for diagnosis of deep endometriosis involving uterosacral ligaments, torus uterinus and posterior vaginal fornix: prospective study.

OBJECTIVE: To evaluate the accuracy of transvaginal ultrasound (TVS) in diagnosing deep endometriosis (DE) involving the uterosacral ligaments (USLs), torus uterinus (TU) or posterior vaginal fornix (PVF) in women with suspected endometriosis scheduled for laparoscopic surgery. METHODS: In this prospective study, consecutive women with clinically suspected pelvic endometriosis who were scheduled for laparoscopic surgery were invited to participate. TVS was performed before surgery. TVS findings were compared with those obtained at laparoscopy and confirmed histologically. The accuracy of TVS for diagnosing DE involving the USLs, TU or PVF was assessed. Additionally, the association of DE involving the USLs, TU or PVF on TVS with symptoms and with DE affecting other pelvic locations was assessed. RESULTS: In total, 172 patients were included. The global sensitivity and specificity of TVS in diagnosing DE affecting the USLs, TU and/or PVF were 92% and 87%, respectively. For DE involving the USLs, the accuracy, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), positive likelihood ratio and negative likelihood ratio of TVS were 89.5%, 96.6%, 82.1%, 85.0%, 95.8%, 5.41 and 0.04, respectively; the respective values for DE involving the TU were 86.6%, 83.9%, 89.4%, 89.0%, 84.4%, 7.92 and 0.18, and the respective values for DE involving the PVF were 93.6%, 87.0%, 94.6%, 71.4%, 97.9%, 16.20 and 0.14. Logistic regression analysis showed a significant association between DE affecting the USLs, TU and/or PVF and DE affecting the rectosigmoid (odds ratio, 5.43; P < 0.001). Dyschezia was associated strongly with DE involving the USLs, TU and PVF, while dysmenorrhea was associated significantly with DE involving the TU. CONCLUSION: TVS has high accuracy, sensitivity, specificity, PPV and NPV for the detection of DE involving the USLs, TU and PVF in women with suspected endometriosis scheduled for laparoscopic surgery. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.