Management of hereditary hemorrhagic telangiectasia-like symptoms induced by trastuzumab emtansine in a breast cancer patient: case report.

Trastuzumab emtansine (T-DM1) is a targeted therapy combining trastuzumab and emtansine for human epidermal growth factor receptor 2(HER2)-positive breast cancer, with common side effects including fatigue, nausea, pain, headache, low platelet count, and elevated liver enzymes. Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant vascular dysplasia characterized by vascular malformations and telangiectasias in various organs. We present a case of a female patient with advanced breast cancer who developed HHT-like symptoms while on T-DM1 treatment. A 59-year-old woman treated with radiotherapy and T-DM1 every 21 days developed recurring nosebleeds and mucocutaneous and liver telangiectasias indistinguishable from HHT three months after receiving the first dose of T-DM1. Other organ vascular malformations were ruled out through screening protocols. The patient had no previous HHT symptoms or family history. Nasal care measures like lubrication and antifibrinolytics (tranexamic acid) were provided. In addition, propranolol was also prescribed due to its antiangiogenic and antitumoral properties, leading to significantly decreased epistaxis and telangiectasias. Microtubule disruptions caused by T-DM1, along with other angiogenic mechanisms may contribute to the development of telangiectasias resembling HHT. The use of propranolol, an initial approach for HHT, proved to be effective in this case. It is crucial for oncologists and HHT specialists to be aware of this rare adverse event associated with T-DM1 and to implement appropriate management strategies.

Analyzing Neoadjuvant Chemotherapy Effects in HER2-Low Breast Cancer: Real World Data.

PURPOSE: Neoadjuvant chemotherapy (NAC) can be used as upfront therapy in aggressive breast cancer (BC). human epidermal growth factor receptor 2 (HER2)-low BC, defined as tumors scoring +1 or +2 on immunohistochemistry without HER2 gene amplification by in situ hybridization, lacks information on real-world data (RWD) outcomes, especially in the NAC setting. This subgroup, which does not reach the HER2 positive criteria due to its lower receptor expression, represents a distinct clinical category potentially requiring tailored therapeutic approaches. STUDY OBJECTIVE:  The objective of this study is to characterize patients with BC with HER2-low status who received NAC in a Brazilian public reference center for female tumors and key outcomes such as pathological complete response (pCR), overall survival (OS), and metastasis-free survival (MFS). METHODS: A retrospective cohort study based on a large BC database from a reference cancer center in Brazil. Patients with BC that received NAC, diagnosed between 2011 and 2020, were included if they presented HER2-low status (defined as tumors scoring +1 or +2 on immunohistochemistry without HER2 gene amplification by in situ hybridization) and had complete data on outcomes. Clinical and demographic data were collected, such as age, menopausal status, Ki-67, hormone receptor expression and others. Key outcomes from the study comprised pCR (defined as ypT0/TIs/ypN0), overall survival, and metastasis-free survival (MFS). Survival analyses were conducted through the semiparametric Kaplan-Meier method to assess OS and MFS by pCR status, considering BC diagnosis as the index date. RESULTS: Overall, 297 patients were eligible and 141 were included in the study after matching the HER2-low definition. The pCR was seen in 18 out of 141 patients (12.7%). The median overall survival was 8.2 years, and the median MFS was 2.7 years. The OS of pCR was 83.4% and non-pCR was 58.1%; the DFS of pCR was 55.5% and non-pCR 40.6%. CONCLUSION: This study gives updated insights on pCR, OS, and MFS in women with HER2-low BC exposed to NAC.

Racial/Ethnic Differences in Pathologic Complete Response to Neoadjuvant Chemotherapy and Survival Among Early-Stage, Erb-B2 Receptor Tyrosine Kinase 2-Low Breast Cancer Patients.

Racial/ethnic differences in pathologic complete response (pCR), and in overall survival (OS) by pCR status, among early-stage, erb-b2 receptor tyrosine kinase 2 (ERBB2)-low breast cancer patients after neoadjuvant chemotherapy (NACT) are unknown. Data were from the 2010-2020 National Cancer Database that included Asian/Pacific Islander (API), American Indian/Alaska Native/Other (AIANO), Black, Hispanic, and White patients. pCR and OS were modeled using logistic regression and Cox regression, respectively. Of 25,577 patients, Black patients achieved a 17.4% pCR rate, Hispanic 16.0%, White 14.7%, API 13.5%, and AIANO 10.9%. AIANO patients had lower odds of pCR than White patients (adjusted odds ratio, 0.66; 95% confidence interval [CI], 0.48-0.91). Among patients without pCR, API (adjusted hazard ratio [aHR], 0.62; 95% CI, 0.51-0.76) and Hispanic (aHR, 0.77; 95% CI, 0.67-0.89) patients had lower mortality risks than White patients. Among patients with pCR, similar OS rates were observed between Hispanic (aHR, 1.08; 95% CI, 0.66-1.78), Black (aHR, 0.77; 95% CI, 0.55-1.09), API (aHR, 0.41; 95% CI, 0.15-1.12), or AIANO (aHR, 0.35; 95% CI, 0.05-2.50) and White patients. Post-NACT pCR rates were similar across racial/ethnic groups of early-stage, ERBB2-low breast cancer patients. Among patients without pCR, API and Hispanic patients had better OS; among patients with pCR, there was no differential OS by race/ethnicity. Our findings suggest the need for longitudinal studies of OS differences in this patient population.

Noninvasive identification of HER2-low-positive status by MRI-based deep learning radiomics predicts the disease-free survival of patients with breast cancer.

OBJECTIVE: This study aimed to establish a MRI-based deep learning radiomics (DLR) signature to predict the human epidermal growth factor receptor 2 (HER2)-low-positive status and further verified the difference in prognosis by the DLR model. METHODS: A total of 481 patients with breast cancer who underwent preoperative MRI were retrospectively recruited from two institutions. Traditional radiomics features and deep semantic segmentation feature-based radiomics (DSFR) features were extracted from segmented tumors to construct models separately. Then, the DLR model was constructed to assess the HER2 status by averaging the output probabilities of the two models. Finally, a Kaplan‒Meier survival analysis was conducted to explore the disease-free survival (DFS) in patients with HER2-low-positive status. The multivariate Cox proportional hazard model was constructed to further determine the factors associated with DFS. RESULTS: First, the DLR model distinguished between HER2-negative and HER2-overexpressing patients with AUCs of 0.868 and 0.763 in the training and validation cohorts, respectively. Furthermore, the DLR model distinguished between HER2-low-positive and HER2-zero patients with AUCs of 0.855 and 0.750, respectively. Cox regression analysis showed that the prediction score obtained using the DLR model (HR, 0.175; p = 0.024) and lesion size (HR, 1.043; p = 0.009) were significant, independent predictors of DFS. CONCLUSIONS: We successfully constructed a DLR model based on MRI to noninvasively evaluate the HER2 status and further revealed prospects for predicting the DFS of patients with HER2-low-positive status. CLINICAL RELEVANCE STATEMENT: The MRI-based DLR model could noninvasively identify HER2-low-positive status, which is considered a novel prognostic predictor and therapeutic target. KEY POINTS: • The DLR model effectively distinguished the HER2 status of breast cancer patients, especially the HER2-low-positive status. • The DLR model was better than the traditional radiomics model or DSFR model in distinguishing HER2 expression. • The prediction score obtained using the model and lesion size were significant independent predictors of DFS.

Cáncer de mama en el norte del Perú: subtipos moleculares y HER2 low / Breast cancer in northern Peru: molecular subtypes and HER2 low

RESUMEN El objetivo del estudio fue conocer el perfil inmunohistoquímico del cáncer de mama e identificar el subgrupo HER2 low en la macrorregión norte del Perú. Se realizó un estudio transversal con una muestra de 1176 pacientes atendidos en el Instituto Regional de Enfermedades Neoplásicas Norte del Perú desde enero de 2016 a diciembre de 2023. Los datos recolectados (edad, tipo histológico, grado y resultados complementarios), se analizaron con frecuencias y porcentajes. El perfil correspondió a: luminal B (45,6%); luminal A (24,7%); triple negativo (18,2%); y HER2 positivo no luminal (11,5%). Además, HER2 low fueron 215 pacientes (25,1% de los considerados previamente negativos). Este estudio proporciona evidencia que la subtipificación de cáncer de mama ha cambiado, siendo luminal B más frecuente, y es esencial involucrar a políticas de salud para adquirir terapias dirigidas considerando a pacientes HER2 low.

ABSTRACT This study aimed to understand the immunohistochemical profile of breast cancer and to identify the HER2 low subgroup in the northern macro-region of Peru. A cross-sectional study was conducted in 1176 patients from the Regional Institute of Neoplastic Diseases Northern Peru, from January 2016 to December 2023. We analyzed the data (age, histological type, grade and complementary results), with frequencies and percentages. The profile corresponded to: luminal B (45.6%); luminal A (24.7%); triple negative (18.2%); and HER2 positive non luminal (11.5%). In addition, 215 patients presented HER2 low (25.1% of those previously considered negative). This study provides evidence that the subtyping of breast cancer has changed, being luminal B the most frequent. It is essential to involve health policies to acquire targeted therapies considering HER2 low patients.

Characterization of Expression and Function of the Formins FHOD1, INF2, and DAAM1 in HER2-Positive Breast Cancer.

PURPOSE: Human epidermal growth factor receptor 2 (HER2)-targeted therapies, such as trastuzumab, benefit patients with HER2-positive metastatic breast cancer; however, owing to traditional pathway activation or alternative signaling, resistance persists. Given the crucial role of the formin family in shaping the actin cytoskeleton during cancer progression, these proteins may function downstream of the HER2 signaling pathway. Our aim was to uncover the potential correlations between formins and HER2 expression using a combination of public databases, immunohistochemistry, and functional in vitro assays. METHODS: Using online databases, we identified a negative prognostic correlation between specific formins mRNA expression in HER2-positive cancers. To validate these findings at the protein level, immunohistochemistry was performed on HER2 subtype breast cancer tumors to establish the links between staining patterns and clinical characteristics. We then knocked down individual or combined formins in MDA-MB-453 and SK-BR-3 cells and investigated their effects on wound healing, transwell migration, and proliferation. Furthermore, we investigated the effects of erb-b2 receptor tyrosine kinase 2 (ERBB2)/HER2 small interfering RNA (siRNA)-mediated knockdown on the PI3K/Akt and MEK/ERK1 pathways as well as on selected formins. RESULTS: Our results revealed that correlations between INF2, FHOD1, and DAAM1 mRNA expression and ERBB2 in HER2-subtype breast cancer were associated with worse outcomes. Using immunohistochemistry, we found that high FHOD1 protein expression was linked to higher histological grades and was negatively correlated with estrogen and progesterone receptor positivity. Upon formins knockdown, we observed effects on wound healing and transwell migration, with a minimal impact on proliferation, which was evident through single and combined knockdowns in both cell lines. Notably, siRNA-mediated knockdown of HER2 affected FHOD1 and INF2 expression, along with the phosphorylated Akt/MAPK states. CONCLUSION: Our study highlights the roles of FHOD1 and INF2 as downstream effectors of the HER2/Akt and HER2/MAPK pathways, suggesting that they are potential therapeutic targets in HER2-positive breast cancer.

Challenges and future of HER2-positive gastric cancer therapy.

Gastric cancer is the fifth most common cancer worldwide, and the treatment of advanced gastric cancer has relatively little progress. With the continuous development of molecularly targeted therapy for tumors, it has been discovered that human epidermal growth factor receptor 2 (HER2) contributes to the poor prognosis and pathogenesis of various cancers. In order to treat HER2-positive advanced gastric cancer, Trastuzumab has emerged as the first first-line targeted medication used in conjunction with chemotherapy. The consequent trastuzumab resistance has become an important issue, and various new HER2-targeted gastric cancer drugs are emerging to address this challenge. This review's primary concern is the drug mechanism of various HER2-positive gastric cancer targeted therapy and fresh techniques of detection.

Tratamiento sistémico para el cáncer de mama HER2 positivo avanzado. Revisión de la evidencia y abordaje terapéutico en el Instituto Nacional de Cancerología - Colombia / Systemic treatment for advanced HER2 positive breast cancer. Review of the evidence and therapeutic approach at the Instituto Nacional de Cancerología - Colombia

El cáncer de mama es la neoplasia más frecuente y de mayor mortalidad en las mujeres en todo el mundo. El receptor 2 del factor de crecimiento epidérmico humano (HER2) se sobreexpresa en aproximadamente el 20% de las pacientes con cáncer de mama y se asocia a mayor riesgo de recidiva tumoral y mortalidad. Antes del desarrollo de los anticuerpos monoclonales dirigidos contra HER2, el cáncer de mama HER2 positivo estaba asociado con un pronóstico desfavorable. El uso de las terapias dirigidas anti HER2 ha mejorado significativamente las tasas de supervivencia global tanto en el escenario adyuvante como en la enfermedad metastásica. En los últimos años han surgido nuevos medicamentos que bloquean esta vía de señalización, lo cual ha permitido establecer varias líneas de tratamiento con terapia anti HER2 en las pacientes con enfermedad metastásica. Por esta razón, las unidades funcionales de Oncología Clínica/Seno y Tejidos Blandos tomaron la decisión de realizar una revisión de la evidencia científica disponible a octubre de 2021, para establecer las recomendaciones en el abordaje terapéutico de las pacientes con cáncer de mama metastásico HER2 positivo en el Instituto Nacional de Cancerología (INC).

Breast cancer is the most common neoplasm and the one with the highest mortality in women worldwide. Human epidermal growth factor receptor 2 (HER2) is overexpressed in approximately 20% of breast cancer patients and is associated with an increased risk of tumor recurrence and mortality. Before the development of monoclonal antibodies directed against HER2, HER2-positive breast cancer was associated with a poor prognosis. The use of anti-HER2 targeted therapies has significantly improved overall survival rates both in the adjuvant setting and in metastatic disease. In recent years, new drugs have emerged that block this signaling pathway, which has made it possible to establish several lines of treatment with anti-HER2 therapy in patients with metastatic disease. For this reason, the clinical oncology/breast and soft tissue functional units made the decision to conduct a review of the available scientific evidence as of October 2021 to establish recommendations for the therapeutic approach to patients with HER2-positive metastatic breast cancer in the National Cancer Institute (INC).

Indicaciones para el uso de pertuzumab en cáncer de mama HER2 positivono metastásico en los escenarios neoadyuvante y adyuvante. Revisión de la evidencia y abordaje terapéutico en el Instituto Nacional de Cancerología - Colombia / Indications for the use of pertuzumab in non-metastatic HER2-positive breast cancer in the neoadjuvant and adjuvant. Review of the literature and therapeutic approach at the Instituto Nacional de Cancerología - Colombia

La adición de la terapia dirigida a la quimioterapia citotóxica en pacientes con cáncer de mama ha mejorado significativamente los desenlaces oncológicos en las pacientes con tumores HER2 positivo. El uso de pertuzumab durante el manejo neoadyuvante incrementa significativamente la respuesta patológica completa y en la actualidad permite emplear regímenes libres de antraciclinas con una eficacia similar y menores efectos cardiovasculares (en especial sobre la fracción de eyección). El beneficio en supervivencia libre de enfermedad invasiva, de adicionar pertuzumab en el escenario adyuvante en las pacientes sin tratamiento anti HER2 previo, está limitado a aquellas con ganglios positivos. La implementación de esquemas con bloqueo dual anti HER2, durante el tratamiento inicial del cáncer de mama HER2 positivo, mejora significativamente el pronóstico oncológico en este grupo de pacientes.

The addition of targeted therapy to cytotoxic chemotherapy in patients with breast cancer has significantly improved oncologic outcomes in patients with HER2-positive tumors. The use of pertuzumab during neoadjuvant management significantly increases the complete pathological response and currently allows the use of anthracycline-free regimens with similar efficacy and fewer cardiovascular effects (especially on ejection fraction). The benefit of pertuzumab in disease-free survival in the adjuvant setting for patients without prior anti-HER2 treatment is limited to those with positive nodes. The implementation of schemes with dual anti-HER2 blockade during the initial treatment of HER2-positive breast cancer significantly improves the oncological outcomes in this group of patients.

Análisis de la coexpresión de HER2/GRB7 y su asociación con variables clinicopatológicas en un grupo de mujeres colombianas con diagnóstico de cáncer de mama invasivo / Analysis of HER2/GRB7 co-expression and its association with clinicopathological variables in a group of Colombian women diagnosed with invasive breast cancer

Objetivo. Analizar las diferencias en la presentación de variables clínico-patológicas, de acuerdo con la expresión proteica de GRB7, en tumores HER2 positivos en mujeres colombianas con cáncer de mama invasivo, diagnosticado entre los años 2013 y 2015 en el Instituto Nacional de Cancerología E.S.E (INC). Métodos. Se incluyeron 158 pacientes con diagnóstico confirmado de cáncer de mama ductal invasivo. Se evaluó la expresión de los receptores hormonales (receptor de estrógeno (RE) y de progesterona (RP)), HER2, Ki67 y GRB7, mediante inmunohistoquímica (IHQ), y a partir de estos, se clasificaron los tumores en subtipos intrínsecos. Los análisis estadísticos incluyeron las pruebas de Chi-cuadrado/test exacto de Fisher para las variables categóricas, y la prueba U Mann Whitney/ Kruskal Wallis para las variables cuantitativas. Se evaluó la supervivencia global (SG) y libre de enfermedad (SLR) según la coexpresión de HER2/GRB7 usando el método de Kaplan-Meier y el test de log-rank. Resultados. La expresión de GRB7 se observó exclusivamente en tumores HER2-positivos (luminal B/HER2+ y HER2-enriquecidos: p<0,001). Los casos HER2+/GRB7+ mostraron una mayor expresión de Ki67 (40% vs. 27,5%, p=0,029), pero una tendencia a presentar un menor tamaño tumoral (30 mm vs. 51 mm, p=0,097), comparado con los tumores HER2+/GRB7-. No obstante, no se observaron diferencias en la supervivencia según la coexpresión de HER2/GRB7 (SG: p=0,6; SLR: p=0,07). Conclusiones. En nuestra muestra de estudio, la expresión de GRB7 en tumores HER2+ no se asoció con características clínico-patológicas de pronóstico desfavorable.

Objective: To analyze differences in the presentation of clinicopathological variables according to GRB7 protein expression in HER2-positive tumors in Colombian patients with invasive ductal breast carcinomas diagnosed between 2013 and 2015 at the Instituto Nacional de Cancerología (Bogotá, Colombia).Methods: A total of 158 breast cancer patients were included with a confirmed diagnosis of invasive ductal carcinoma. A single pathologist evaluated the protein expression of hormone receptors (estrogen (ER) and progesterone receptor (PR)), HER2, Ki67, and GRB7 by immunohistochemistry (IHC). The chi-square and Fisher's exact tests were used to assess differences between categorical variables, as well as the Mann-Whitney/Kruskal-Wallis U test for numerical variables. Overall (OS) and disease-free (DFS) survival were evaluated according to HER2/GRB7 co-expression using the Kaplan-Meier method and log-rank test.Results:GRB7 expression was observed exclusively in HER2-positive tumors (luminal B/HER2+ and HER2-enriched: p<0.001). HER2+/GRB7+ cases showed higher Ki67 expression (40% vs. 27.5%, p=0.029) and a tendency to present a smaller tumor (30 mm vs. 51 mm, p=0.097) compared to HER2+/GRB7- tumors. However, no differences in OS or DFS were observed by HER2/GRB7 co-expression (OS: p=0.6; DFS: p=0.07).Conclusions:Our results in Colombian patients indicate that GRB7 expression in HER2-positive breast tumors is not associated with unfavorable clinicopathological features.

Age-specific impacts of nicotine and withdrawal on hippocampal neuregulin signalling.

Smoking remains the leading cause of preventable death in the United States, with 87% of smokers starting before the age of 18. Age of initiation is a major predictive factor for smoking frequency and successful smoking cessation. People who initiate smoking during adolescences are 2.33 times more likely to become heavy smokers and half as likely to quit compared with smokers who started during adulthood. Additionally, schizophrenia, a disease state linked to altered neurodevelopment during adolescence, is a major predictive factor for smoking status. Smoking rates among people suffering from schizophrenia are between 60% and 90%. Interestingly, the Neuregulin Signalling Pathway (NSP), which plays an important role in neurodevelopment, is implicated in both schizophrenia and nicotine use disorder. Specifically, SNPS in neuregulin 3 (Nrg3) and Erb-B2 Receptor Tyrosine Kinase 4 (ErbB4) have been associated with smoking cessation outcomes and schizophrenia. Here, we examine the effects of chronic nicotine (18 mg/kg/day) and 24-h withdrawal on NSP gene expression in the hippocampus of adult (20-week-old) and adolescent (4-week-old) mice. We show that withdrawal from chronic nicotine decreased the expression of Erbb4 mRNA in the hippocampus of the adult mice but increased the expression of cytosolic Erbb4 protein in adolescent mice. Nrg3 mRNA and protein expression was not altered by chronic nicotine or withdrawal in the adult or adolescent cohorts, but Nrg3 mRNA and synaptosomal protein expression was lower in the adult withdrawal group when compared with their adolescent counterparts. These results highlight the age-specific effects of nicotine withdrawal on the NSP and may contribute to the lower quit rate and higher cigarette consumption of smokers who initiation during adolescences.

Safety and efficacy of adjuvant subcutaneous trastuzumab in human epidermal growth factor receptor 2-positive early breast cancer: Final results of the SafeHER study.

AIM: To report the final results of the 5-year follow-up of the non-randomized SafeHER Phase III study (NCT01566721) describing the safety, tolerability, and efficacy of subcutaneous (SC) trastuzumab alone and in combination with concurrent or sequential chemotherapy. METHODS: Patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (EBC) with no prior anti-HER2 therapy were included. SC trastuzumab was administered every 3 weeks for 18 cycles as adjuvant therapy with or without chemotherapy (concurrent or sequential). The primary objective was overall safety and tolerability of SC trastuzumab; efficacy was a secondary objective. RESULTS: No new safety signals were observed during the final evaluation. The majority of adverse events (AEs) were grade 1 or 2 across the chemotherapy subgroups. Treatment discontinuation due to AEs was 5.1% for the intent-to-treat (ITT) population and similar for all chemotherapy subgroups. The overall disease-free survival (DFS) 5-year event-free rate in the ITT population (n = 2573) was 86.6% (95% CI, 85.2%-87.9%) with a median follow-up of 72 months. Based on chemotherapy timing, the no (n = 235), concurrent (n = 1533), and sequential (n = 805) chemotherapy subgroups had DFS 5-year event-free rates (95% CI) of 88.5% (83.4%-92.2%), 88.4% (86.6%-89.9%), and 82.6 (79.7%-85.2%), respectively. CONCLUSIONS: The 5-year follow-up analysis of the SafeHER trial demonstrating that SC trastuzumab has an acceptable safety profile, including cardiac toxicity, and efficacy for the treatment of HER2-positive EBC with and without chemotherapy, corresponding with historical data with trastuzumab.

Association of genetic ancestry with HER2, GRB7 AND estrogen receptor expression among Colombian women with breast cancer.

Background: Our previous study reported higher mRNA levels of the human epidermal growth factor receptor 2 (HER2)-amplicon genes ERBB2 and GRB7 in estrogen receptor (ER)-positive breast cancer patients with relatively high Indigenous American (IA) ancestry from Colombia. Even though the protein expression of HER2 and GRB7 is highly correlated, they may also express independently, an event that could change the patients' prognosis. In this study, we aimed to explore the differences in ER, HER2 and GRB7 protein expression according to genetic ancestry, to further assess the clinical implications of this association. Methods: We estimated genetic ancestry from non-tumoral breast tissue DNA and assessed tumoral protein expression of ER, HER2, and GRB7 by immunohistochemistry in a cohort of Colombian patients from different health institutions. We used binomial and multinomial logistic regression models to test the association between genetic ancestry and protein expression. Kaplan-Meier and log-rank tests were used to evaluate the effect of HER2/GRB7 co-expression on patients' survival. Results: Our results show that patients with higher IA ancestry have higher odds of having HER2+/GRB7- breast tumors, compared to the HER2-/GRB7- subtype, and this association seems to be stronger among ER-positive tumors (ER+/HER2+/GRB7-: OR=3.04, 95% CI, 1.47-6.37, p<0.05). However, in the multivariate model this association was attenuated (OR=1.80, 95% CI, 0.72-4.44, p=0.19). On the other hand, it was observed that having a higher European ancestry patients presented lower odds of ER+/HER2+/GRB7- breast tumors, this association remained significant in the multivariate model (OR=0.36, 95% CI, 0.13 - 0.93, p= 0.0395). The survival analysis according to HER2/GRB7 co-expression did not show statistically significant differences in the overall survival and recurrence-free survival. Conclusions: Our results suggest that Colombian patients with higher IA ancestry and a lower European fraction have higher odds of ER+/HER2+/GRB7- tumors compared to ER+/HER2-/GRB7- disease. However, this association does not seem to be associated with patients' overall or recurrence-free survival.

Tumor-Infiltrating Lymphocytes in Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer Receiving Neoadjuvant Docetaxel, Carboplatin, Trastuzumab, and Pertuzumab.

PURPOSE: The tumor-infiltrating lymphocytes (TILs) expression in breast cancer is a positive prognostic marker for certain breast cancer subtypes. We evaluated the efficacy of dual anti-human epidermal growth factor receptor 2 (HER2) blockade in HER2-positive breast cancer and hypothesized that high TILs tumors are associated with better outcomes. METHODS: A total of 176 patients who were treated with neoadjuvant docetaxel, carboplatin, trastuzumab, and pertuzumab (TCHP) between December 2015 and December 2018 were reviewed. They were grouped based on a cut-off value of the stromal TILs grade (≤ 20% TILs, > 20% TILs). RESULTS: In total, 107 patients (60.8%) achieved pathological complete response (pCR). Hormone receptor (HR)-negativity (p = 0.001) and a high TILs grade (p = 0.022) were independent predictors of pCR. Among the HR-negative patients, high TILs tumors were significantly associated with pCR (p = 0.035). CONCLUSION: HR status and the TILs grade are significantly correlated with pCR in dual anti-HER2 neoadjuvant therapy. The evaluation of the TILs at baseline may be beneficial for predicting pCR in HER2-positive breast cancer.

Efficacy of Neratinib Plus Capecitabine in the Subgroup of Patients with Central Nervous System Involvement from the NALA Trial.

BACKGROUND: Neratinib has efficacy in central nervous system (CNS) metastases from HER2-positive metastatic breast cancer (MBC). We report outcomes among patients with CNS metastases at baseline from the phase III NALA trial of neratinib plus capecitabine (N + C) versus lapatinib plus capecitabine (L + C). MATERIALS AND METHODS: NALA was a randomized, active-controlled trial in patients who received two or more previous HER2-directed regimens for HER2-positive MBC. Patients with asymptomatic/stable brain metastases (treated or untreated) were eligible. Patients were assigned to N + C (neratinib 240 mg per day, capecitabine 750 mg/m2 twice daily) or L + C (lapatinib 1,250 mg per day, capecitabine 1,000 mg/m2 twice daily) orally. Independently adjudicated progression-free survival (PFS), overall survival (OS), and CNS endpoints were considered. RESULTS: Of 621 patients enrolled, 101 (16.3%) had known CNS metastases at baseline (N + C, n = 51; L + C, n = 50); 81 had received prior CNS-directed radiotherapy and/or surgery. In the CNS subgroup, mean PFS through 24 months was 7.8 months with N + C versus 5.5 months with L + C (hazard ratio [HR], 0.66; 95% confidence interval [CI], 0.41-1.05), and mean OS through 48 months was 16.4 versus 15.4 months (HR, 0.90; 95% CI, 0.59-1.38). At 12 months, cumulative incidence of interventions for CNS disease was 25.5% for N + C versus 36.0% for L + C, and cumulative incidence of progressive CNS disease was 26.2% versus 41.6%, respectively. In patients with target CNS lesions at baseline (n = 32), confirmed intracranial objective response rates were 26.3% and 15.4%, respectively. No new safety signals were observed. CONCLUSION: These analyses suggest improved PFS and CNS outcomes with N + C versus L + C in patients with CNS metastases from HER2-positive MBC. IMPLICATIONS FOR PRACTICE: In a subgroup of patients with central nervous system (CNS) metastases from HER2-positive breast cancer after two or more previous HER2-directed regimens, the combination of neratinib plus capecitabine was associated with improved progression-free survival and CNS outcomes compared with lapatinib plus capecitabine. These findings build on previous phase II and III studies describing efficacy of neratinib in the prevention and treatment of CNS metastases, and support a role for neratinib as a systemic treatment option in the management of patients with HER2-positive brain metastases following antibody-based HER2-directed therapies.

Prediction of breast cancer molecular subtypes on DCE-MRI using convolutional neural network with transfer learning between two centers.

OBJECTIVES: To apply deep learning algorithms using a conventional convolutional neural network (CNN) and a recurrent CNN to differentiate three breast cancer molecular subtypes on MRI. METHODS: A total of 244 patients were analyzed, 99 in training dataset scanned at 1.5 T and 83 in testing-1 and 62 in testing-2 scanned at 3 T. Patients were classified into 3 subtypes based on hormonal receptor (HR) and HER2 receptor: (HR+/HER2-), HER2+, and triple negative (TN). Only images acquired in the DCE sequence were used in the analysis. The smallest bounding box covering tumor ROI was used as the input for deep learning to develop the model in the training dataset, by using a conventional CNN and the convolutional long short-term memory (CLSTM). Then, transfer learning was applied to re-tune the model using testing-1(2) and evaluated in testing-2(1). RESULTS: In the training dataset, the mean accuracy evaluated using tenfold cross-validation was higher by using CLSTM (0.91) than by using CNN (0.79). When the developed model was applied to the independent testing datasets, the accuracy was 0.4-0.5. With transfer learning by re-tuning parameters in testing-1, the mean accuracy reached 0.91 by CNN and 0.83 by CLSTM, and improved accuracy in testing-2 from 0.47 to 0.78 by CNN and from 0.39 to 0.74 by CLSTM. Overall, transfer learning could improve the classification accuracy by greater than 30%. CONCLUSIONS: The recurrent network using CLSTM could track changes in signal intensity during DCE acquisition, and achieved a higher accuracy compared with conventional CNN during training. For datasets acquired using different settings, transfer learning can be applied to re-tune the model and improve accuracy. KEY POINTS: • Deep learning can be applied to differentiate breast cancer molecular subtypes. • The recurrent neural network using CLSTM could track the change of signal intensity in DCE images, and achieved a higher accuracy compared with conventional CNN during training. • For datasets acquired using different scanners with different imaging protocols, transfer learning provided an efficient method to re-tune the classification model and improve accuracy.

A population-based comparison of treatment, resource utilization, and costs by cancer stage for Ontario patients with HER2-positive breast cancer.

PURPOSE: We sought to expand the currently limited, Canadian, population-based data on the characteristics, treatment pathways, and health care costs according to stage in patients with human epidermal growth factor receptor-2 positive (HER2+) breast cancer (BC). METHODS: We extracted data from the publicly funded health care system in Ontario. Baseline characteristics, treatment patterns, and health care costs were descriptively compared by cancer stage (I-III vs. IV) for adult women diagnosed with invasive HER2+ BC between 2012 and 2016. Resource use was multiplied by unit costs for publicly funded health care services to calculate costs. RESULTS: Overall, 4535 patients with stage I-III and 354 with stage IV HER2+ BC were identified. Most patients with stage I-III disease were treated with surgery (4372, 96.4%), with the majority having a lumpectomy, and 3521 (77.6%) received radiation. Neoadjuvant (NAT) and adjuvant (AT) systemic treatment rates were 20.1% (n = 920) and 88.8% (n = 3065), respectively. Systemic treatment was received by 311 patients (87.9%) with metastatic HER2+ BC, 264 of whom (84.9%) received trastuzumab. Annual health care costs per patient were nearly 3 times higher for stage IV vs. stage I-III HER2+ BC. CONCLUSION: Per-patient annual costs were substantially higher for women with metastatic HER2+ BC, despite less frequent exposure to surgery and radiation compared to those with early stage disease. Increasing NAT rates in early stage disease represent a critical opportunity to prevent recurrence and reduce the costs associated with treating metastatic HER2+ BC.

Tratamiento Neoadyuvante en cáncer de mama HER2 positivo. La era de la terapia dirigida / Neoadjuvant treatment in HER2 positive breast cancer. The Age of Targeted Therapy

Introducción: El tratamiento neodyuvante del cáncer de mama HER2 positivo ha ido evolucionando a través del tiempo, con la implementación de nuevas estrategias de manejo terapéutico. Es de esta manera como el trastuzumab, un anticuerpo monoclonal anti-HER2sigue siendo el tratamiento estándar en este subtipo de cáncer, los primeros estudios en los que se evidencia su eficacia son el realizado por el Dr. Buzdar y el estudio NOAH en los cuales las pacientes alcanzaron mayores tasas de respuesta patológica completa en comparación con quimioterapia sola, así como también un mayor número de cirugías conservadoras de mama en lugar de mastectomía.Con el paso de los años se han ido desarrollando nuevas estrategias de manejo terapéutico, así tenemos el doble bloqueo anti-HER2 con los anticuerpos monoclonales trastuzumab y pertuzumab que han mejorado las tasas de respuesta patológica completa. Además se ha incluido al lapatinib un inhibidor de tirosina quinasa como parte de las terapias dirigidas. Se ha dilucidado si las antraciclinas confieren un beneficio adicional al tratamiento neoadyuvante y los estudios demuestran que el beneficio es el mismo queotros esquemas de quimioterapia. Es en realidad la quimioterapia indispensable en la neoadyuvancia, el estudio PHERGain demuestra que existen pacientes que pueden alcanzar respuesta patológica completa solo con el doble bloqueo anti-her2 (trastuzumab y pertuzumab) lo que evitaría la toxicidad innecesaria por quimioterapia, y se podrían desarrollar estrategias para el manejo de aquellas pacientes que no alcanzaron una respuestapatológica completa posterior al doble bloqueo. Aún queda un campo amplio por explorar y con estudios en curso al momento. Palabras claves:DsCS:Receptor ErbB-2, Trastuzumab, Neoplasias de la Mama, Quimioterapia Adyuvante, Ado-Trastuzumab Emtansina

Introduction:The neodyuvanttreatment of HER2 positive breast cancer has evolved over time, with the implementation of new therapeutic management strategies. It is in this way that trastuzumab, an anti-HER2 monoclonal antibody continues to be the standard treatment in this subtype of cancer, the first studies in which its efficacy is evidenced are the one carried out by Dr. Buzdar and the NOAH study in which patients achieved higher rates of complete pathological response compared to chemotherapy alone, as well as a higher number of breast-conserving surgeries rather than mastectomy.Over the years, new therapeutic management strategies have been developed, thus we have the double anti-HER2 blockade with the monoclonal antibodies trastuzumab and pertuzumab that have improved the ratesof complete pathological response. In addition, lapatinib, a tyrosine kinase inhibitor, has been included as part of targeted therapies. It has been elucidated whether anthracyclines confer an additional benefit to neoadjuvant treatment and studies show that the benefit is the same as other chemotherapy regimens.It is actually the essential chemotherapy in neoadjuvant therapy, the PHERGain study shows that there are patients who can achieve a complete pathological response only with the double anti-her2 blockade (trastuzumab and pertuzumab), which would avoid unnecessary toxicity due to chemotherapy, and strategies could be developed for the management of those patients who did not achieve a complete pathological response after double blockade. There is still a wide field to explore and with studies underway at the moment. Keywords:MESH:Receptor, ErbB-2;Trastuzumab; Breast Neoplasms; Chemotherapy, Adjuvant; Ado-Trastuzumab Emtansine

Diagnóstico y tratamiento del cáncer de mama HER2+: Guía de Práctica Clínica de la Sociedad Peruana de Cancerología / Diagnosis and treatment of HER2 + breast cancer: Clinical Practice Guide of the Peruvian Society of Cancerology

RESUMEN Introducción. En Perú, el cáncer de mama representa el tipo de cáncer más frecuente en mujeres y el sexto tipo de cáncer más letal en la población general. La sobreexpresión del receptor del factor de crecimiento epidérmico (HER2+) ocurre en 20% a 30% de los cánceres de mama, y se asocia con tumores más agresivos, con mayor recurrencia y mayor mortalidad. Objetivo. Elaborar un conjunto de recomendaciones basadas en evidencias para el diagnóstico y tratamiento del cáncer de mama HER2+, con la finalidad de contribuir a reducir la mortalidad, progresión de la enfermedad y mejorar la calidad de vida. Métodos. Se conformó un panel de especialistas clínicos y metodólogos, quienes identificaron preguntas clínicas relevantes sobre el diagnóstico y tratamiento del cáncer de mama HER2+. Se desarrolló una búsqueda sistemática de GPC en Medline (PubMed), y en organismos elaboradores y recopiladores. Para la formulación de recomendaciones, el panel de especialistas discutió la evidencia y elementos del contexto de implementación de la recomendación, siguiendo la metodología propuesta por el Ministerio de Salud del Perú. Resultados. Se priorizó nueve preguntas clínicas. Se formuló un total de 25 recomendaciones clínicas. Conclusiones. Se elaboró una GPC basada en evidencias, a través de un proceso sistemático, riguroso y transparente desarrollado por un equipo multidisciplinario.

ABSTRACT Introduction. In Peru, breast cancer represents the most common type of cancer in women and the sixth most lethal type of cancer in the general population. Overexpression of the epidermal growth factor receptor (HER2 +) occurs in 20% to 30% of breast cancers, and is associated with more aggressive tumors, with greater recurrence and greater mortality. Objective. Prepare a set of evidence-based recommendations for the diagnosis and treatment of HER2 + breast cancer, in order to help reduce mortality, disease progression and improve quality of life. Methods. A panel of clinical specialists and methodologists was formed, who identified relevant clinical questions about the diagnosis and treatment of HER2 + breast cancer. A systematic search for CPGs was carried out in Medline (PubMed), and in developing and compiling agencies. For the formulation of recommendations, the panel of specialists discussed the evidence and elements of the context of implementation of the recommendation, following the methodology proposed by the Ministry of Health of Peru. Results. Nine clinical questions were prioritized. A total of 25 clinical recommendations were made. Conclusions. An evidence-based CPG was developed through a systematic, rigorous and transparent process developed by a multidisciplinary team.

Relative Survival Benefit by Hormonal Receptor Status of Adding Trastuzumab to Neoadjuvant Chemotherapy in Breast Cancer Patients.

PURPOSE: Neoadjuvant chemotherapy (NAC) involving trastuzumab markedly increases pathologic complete response (pCR) rates in patients with human epidermal growth factor receptor 2-positive (HER2+) breast cancer. Despite increasing pCR rates, long-term survival gains are controversial owing to distinctive biologic behavior mediated by the presence of hormonal receptors (HRs) that may interact with HER2 receptors. We, therefore, investigated the differences in relative survival gain provided by neoadjuvant trastuzumab-based chemotherapy on HR positive (HR+) status of patients. METHODS: We retrospectively analyzed women with stage II or III HER2+ breast cancer who underwent NAC followed by a breast cancer surgery between 2008 and 2013. The survival benefits of adding trastuzumab to NAC were analyzed by classifying patients into HR+ and HR negative (HR-) groups. RESULTS: Of 666 patients included in the study, 374 (52.1%) were HR+ and 319 (47.9%) were HR-. In the HR+ group, trastuzumab treatment led to higher pCR rates and significantly better breast cancer specific survival (BCSS) and overall survival (OS) than no trastuzumab treatment. However, among patients with HR- breast cancer, trastuzumab treatment showed no statistically significant difference between BCSS and OS following multivariate analysis. CONCLUSION: We found that the addition of trastuzumab to NAC improved relative survival benefit in HER2+/HR+ patients than in HER2+/HR- patients, even though the pCR rate increases were lower. Although pCR has been regarded as a surrogate marker for estimating long-term survival benefits after NAC, it alone may not translate into real long-term oncologic outcomes in particular cancer subtypes after trastuzumab-based NAC. Further longer-term evaluation of the objective survival benefit after NAC driven by a dual HER2 block according to HR status is warranted.