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.

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

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.

Multiparametric MR imaging to assess response following neoadjuvant systemic treatment in various breast cancer subtypes: Comparison between different definitions of pathologic complete response.

OBJECTIVES: To validate the performance of multiparametric magnetic resonance (MR) imaging to assess pathologic response to neoadjuvant systemic therapy (NST) in various breast cancer subtypes considering two definitions of pCR: absence of any residual invasive cancer or DCIS (ypT0) and absence of invasive tumour cells (ypT0/is). METHODS: Institutional review board-approved retrospective study, with waiver of the need to obtain informed consent. From January 2015 to June 2017, 81 women with 82 breast cancers undergoing NST were included. Eighteen lesions (22%) were immunohistochemically HER2-positive, 12 (15%) triple negative (TN), 42 (51%) luminal B-like and 10 (12%) luminal B-like/HER2-positive. Breast MR imaging was performed before and after NST. A comparative analysis considering pCR as ypT0 and ypT0/is was carried out. Performance of univariate and multivariate models to potentially predict pathologic response were evaluated. RESULTS: ypT0 was attained in 23% (19/82) of cases and ypT0/is in 33% (27/82) of cases. In both scenarios, HER2-positive subtype achieved the best response, 53% and 48%, respectively. A significant relationship was found between late enhancement and pathologic response (p < 0.001) regardless of pCR definition. In the ypT0 scenario, mean ADC ratio in the pCR subgroup was significantly higher than that in the non-pCR subgroup (p = 0.021) but no significant relationship was noted in ypT0/is. A multivariate model including MR late enhancement, ADC ratio and tumor subtype identified pathologic response with 86% and 84% accuracy when ypT0 and ypT0/is were considered, respectively. CONCLUSION: MR imaging late enhancement and ADC ratio along with breast cancer IHC subtype identify pathologic response following NST with high accuracy, achieving the highest NPV in TN and HER2-positive tumors and the highest PPV in luminal B-like subtypes, regardless of the definition of pCR as ypT0 or ypT0/is. In light of these findings and given that residual DCIS does not have an impact on survival rates, ypT0/is seems to be the preferable definition of pCR.

Resonancia magnética dinámica de mama: estudio comparativo de gadobutrol y Gd-DTPA / Dynamic magnetic resonance imaging of the breast: comparison of gadobutrol vs. Gd-DTPA

Objetivo. Evaluar el perfil farmacocinético del gadobutrol en comparación con el Gd-DTPA, en resonancia magnética de mama con contraste (RM-DC). El objetivo secundario es valorar la eficacia diagnóstica en la detección de lesiones adicionales tumorales en RM-DC, y el perfil de seguridad de ambos contrastes. Material y métodos. Estudio retrospectivo y observacional que incluyó 400 pacientes con diagnóstico histológico de cáncer mamario. A 200 pacientes se les realizó RM-DC con contraste Gd-DTPA (Magnevist®) y a las otras 200 con gadobutrol (Gadovist®). Se analizaron los parámetros farmacocinéticos y la intensidad de señal mediante una ROI (region of interest) en el área intralesional con mayor intensidad de señal en las secuencias poscontraste. Se compararon las variables farmacocinéticas (Ktrans, Kep y Ve) y las curvas de intensidad de señal-tiempo de ambos grupos, así como el número de lesiones adicionales tumorales detectadas con ambos contrastes. Resultados. El realce relativo de intensidad de señal es más alto con gadobutrol que con Gd-DTPA. El gadobutrol muestra significativamente menos lavado (46%) que el Gd-DTPA (58,29%) (p=0,0323). Se observan valores más altos de Ktrans, Kep y Ve para el gadobutrol, siendo la diferencia estadísticamente significativa para los dos primeros parámetros (p=0,001). No se encuentran diferencias en el número de lesiones adicionales malignas confirmadas histológicamente (p=0,387). Conclusiones. El gadobutrol tiene valores más altos de realce, mientras que el Gd-DTPA muestra un lavado más marcado. El gadobutrol no es inferior en cuanto a número de lesiones adicionales malignas detectadas. Ambos contrastes son seguros (AU)

Objective. To compare the pharmacokinetic profile of gadobutrol versus Gd-DTPA in dynamic contrast-enhanced MRI (DCE-MRI) in patients with breast cancer. Secondary objectives included comparing the safety profiles and diagnostic efficacy of the two contrast agents for detecting additional malignant lesions. Material and methods. This retrospective observational study included 400 patients with histologically confirmed breast cancer; 200 underwent DCE-MRI with Gd-DTPA (Magnevist®) and 200 underwent DCE-MRI with gadobutrol (Gadovist®). Pharmacokinetic parameters and signal intensity were analyzed in a region of interest placed in the area within the lesion that had greatest signal intensity in postcontrast sequences. We compared the two groups on pharmacokinetic variables (Ktrans, Kep, and Ve), time-signal intensity curves, and the number of additional malignant lesions detected. Results. The relative signal intensity (enhancement) was higher with gadobutrol than with Gd-DTPA. Washout was lower with gadobutrol than with Gd-DTPA (46% vs. 58,29%, respectively; p=0,0323). Values for Ktrans and Kep were higher for gadobutrol (p=0,001). There were no differences in the number of histologically confirmed additional malignant lesions detected (p=0,387). Conclusions. Relative enhancement is greater with gadobutrol, but washout is more pronounced with Gd-DTPA. The number of additional malignant lesions detected did not differ between the two contrast agents. Both contrasts are safe (AU)

Dynamic magnetic resonance imaging of the breast: Comparison of gadobutrol vs. Gd-DTPA. / Resonancia magnética dinámica de mama: estudio comparativo de gadobutrol y Gd-DTPA.

OBJECTIVE: To compare the pharmacokinetic profile of gadobutrol versus Gd-DTPA in dynamic contrast-enhanced MRI (DCE-MRI) in patients with breast cancer. Secondary objectives included comparing the safety profiles and diagnostic efficacy of the two contrast agents for detecting additional malignant lesions. MATERIAL AND METHODS: This retrospective observational study included 400 patients with histologically confirmed breast cancer; 200 underwent DCE-MRI with Gd-DTPA (Magnevist®) and 200 underwent DCE-MRI with gadobutrol (Gadovist®). Pharmacokinetic parameters and signal intensity were analyzed in a region of interest placed in the area within the lesion that had greatest signal intensity in postcontrast sequences. We compared the two groups on pharmacokinetic variables (Ktrans, Kep, and Ve), time-signal intensity curves, and the number of additional malignant lesions detected. RESULTS: The relative signal intensity (enhancement) was higher with gadobutrol than with Gd-DTPA. Washout was lower with gadobutrol than with Gd-DTPA (46% vs. 58,29%, respectively; p=0,0323). Values for Ktrans and Kep were higher for gadobutrol (p=0,001). There were no differences in the number of histologically confirmed additional malignant lesions detected (p=0,387). CONCLUSIONS: Relative enhancement is greater with gadobutrol, but washout is more pronounced with Gd-DTPA. The number of additional malignant lesions detected did not differ between the two contrast agents. Both contrasts are safe.

Effects of twinning on the subsequent reproductive performance and productive lifespan of high-producing dairy cows.

This study was designed to determine the effects of twinning on the subsequent reproductive performance and productive lifespan of high milk-producing dairy cows. The data analyzed were taken from complete reproductive records for 4861 Holstein Friesian cows comprising a commercial herd, including data for 12 587 calving events from April 1, 2001 to March 31, 2012. The twinning rate was 5.6%, and 9.6% of the cows delivered twins at least once during their life. Conception rates before Days 90, 120, and 300 postpartum were 20.8%, 36.9%, and 74.5%, and 34.2%, 51.8%, and 85.0% for cows delivering twins and singletons, respectively. Cox regression analysis revealed that twinning reduced the chances of conception before Day 90 by a factor of 0.76. Also, the median calving to conception interval was significantly longer for cows calving twins (134 ± 4.5 days) than for cows delivering singletons (108 ± 0.8 days; P < 0.001). Moreover, in cows in which conception was successful, the risk of abortion was higher for cows that calved twins than for those calving singletons (13.7% vs. 10.3%, respectively; P = 0.01). Culling rates before Days 90, 120, and 300 postpartum were 15.6%, 16.1%, and 28.6%, and 7.6%, 8.7%, and 15.9% for cows calving twins and singletons, respectively. Cox regression analysis of the factors affecting the culling rate before Day 300 postpartum revealed a 1.41 times greater hazard ratio of culling for cows calving twins than cows calving singletons. Further, mean productive lifespan was almost 300 days shorter for primiparous twinners (N = 48, 602 ± 493 days) than for nontwinners (N = 2592; 899 ± 581 days; P < 0.01), and 200 days shorter for secundiparous twinners (N = 126, 914 ± 429 days) than for nontwinners undergoing at least two lactations (N = 1936, 1101 ± 522 days; P < 0.01). Kaplan-Meier survival curves for productive lifespan differed between primiparous twinners and non-twinners (P < 0.001), and between secundiparous twinners and nontwinners having at least two lactations (P = 0.017). Differences in culling patterns for twinners and nontwinners were not restricted to the subsequent lactation but continued as long as 800 days after first calving, strongly suggesting long-term negative effects of twinning. As an economic implication of our findings, we suggest that twin embryo reduction at the moment of pregnancy diagnosis could be a profitable strategy to cut twinning rates and abolish their detrimental effects on subsequent reproductive performance and productive lifespan.

Increased risk of tumor seeding after percutaneous radiofrequency ablation for single hepatocellular carcinoma.

Radiofrequency (RF) ablation is an alternative to percutaneous ethanol injection (PEI) for single nonsurgical hepatocellular carcinoma (HCC) and is currently used as adjuvant therapy before liver transplantation. This phase II study assesses the treatment-related complications and response rate of RF for the treatment of single HCC < or = 5 cm. Percutaneous RF was performed under conscious sedation and ultrasound (US) guidance with an electrical generator connected to a single cooled-tip electrode. Neoplastic cells in peripheral blood (reverse transcription-polymerase chain reaction for alpha fetoprotein [AFP] messenger RNA) were analyzed before and after RF. Treatment response was assessed by spiral computed tomography (CT) at 1 month and every 3 months by US or spiral CT thereafter. Thirty-two patients (20 men; age 67 +/- 4 years; 78% hepatitis C virus; 24 Child-Pugh A) with a mean tumor size of 2.8 cm (25 patients < or = 3 cm) were treated by RF (1.25 sessions; mean time, 22.1 +/- 2 minutes). Adjuvant PEI was performed in 9 cases. Complete response was achieved in 21 patients (65%), being significantly higher for HCC < or = 3 cm (76% vs. 29%, P = .03). After a median follow-up of 10 months, 8 patients showed treatment-related morbidity. Four of them (12.5%) showed biopsy-proven needle-track seeding detected between 4 to 18 months. Neoplastic seeding was related to subcapsular location (P = .009), poor differentiation degree (P = .02), and baseline AFP levels (P = .02). Thus, RF ablation with cooled-tip needle for HCC is associated with a high risk of neoplastic seeding. Iatrogenic dissemination was related to subcapsular location or an invasive tumoral pattern, and has to be considered when selecting curative treatments for HCC or adjuvant therapies before liver transplantation.