In-Depth Analysis of the Peripheral Immune Profile of HER2+ Breast Cancer Patients on Neoadjuvant Treatment with Chemotherapy Plus Trastuzumab Plus Pertuzumab.

Currently, therapy for early-stage human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC) is based on the combination of trastuzumab and pertuzumab plus chemotherapy in a neoadjuvant regimen. The INMUNOHER study aimed to detect immunological markers in peripheral blood and their association with treatment response. Sixty-two HER2+ BC patients were recruited. Pre-treatment samples were obtained before the start of treatment, while post-treatment samples were obtained after completing therapy and before surgery and were analyzed by flow cytometry. The pathologic complete response (pCR) rate achieved was 82.3%. The expression of the NKp30, PD-1, and TIM-3 receptors was reduced in the Natural Killer (NK)-CD56dim subset of patients who did not achieve pCR. Following therapy, many changes were found in leukocytes, including alterations in T cell lymphocyte proportions. Also, the percentage of NK cells decreased, and several phenotypic changes were observed in this population. After treatment, IFN-γ production by NK cells against HER2+-cells with or without trastuzumab was significantly reduced. HER2-targeted therapy plus chemotherapy demonstrated high efficacy in most patients, reducing the statistical power for finding immunological markers. However, NK subset phenotypes correlated better with response groups, and numerous changes in the percentage of leukocytes and T and NK cells, as well as changes in the functionality of NK cells, were observed in most patients after treatment, encouraging further research into these immune populations.

Progesterone receptor isoform ratio dictates antiprogestin/progestin effects on breast cancer growth and metastases: A role for NDRG1.

Progesterone receptors (PRs) ligands are being tested in luminal breast cancer. There are mainly two PR isoforms, PRA and PRB, and their ratio (PRA/PRB) may be predictive of antiprogestin response. Our aim was to investigate: the impact of the PR isoform ratio on metastatic behaviour, the PR isoform ratio in paired primary tumours and lymph node metastases (LNM) and, the effect of antiprogestin/progestins on metastatic growth. Using murine and human metastatic models, we demonstrated that tumours with PRB > PRA (PRB-H) have a higher proliferation index but less metastatic ability than those with PRA > PRB (PRA-H). Antiprogestins and progestins inhibited metastatic burden in PRA-H and PRB-H models, respectively. In breast cancer samples, LNM retained the same PRA/PRB ratio as their matched primary tumours. Moreover, PRA-H LNM expressed higher total PR levels than the primary tumours. The expression of NDRG1, a metastasis suppressor protein, was higher in PRB-H compared to PRA-H tumours and was inversely regulated by antiprogestins/progestins. The binding of the corepressor SMRT at the progesterone responsive elements of the NDRG1 regulatory sequences, together with PRA, impeded its expression in PRA-H cells. Antiprogestins modulate the interplay between SMRT and AIB1 recruitment in PRA-H or PRB-H contexts regulating NDRG1 expression and thus, metastasis. In conclusion, we provide a mechanistic interpretation to explain the differential role of PR isoforms in metastatic growth and highlight the therapeutic benefit of using antiprogestins in PRA-H tumours. The therapeutic effect of progestins in PRB-H tumours is suggested.

Increased androgen receptor expression in estrogen receptor-positive/progesterone receptor-negative breast cancer.

PURPOSE: Expression of estrogen receptor alpha (ER) and/or progesterone receptor (PR) defines luminal breast cancer. Even though androgen (AR) and glucocorticoid receptors (GR) are highly expressed in luminal breast cancers, prognostic value remains uncertain and concomitant expression of these four hormone receptors is still unexplored. METHODS: Here, we evaluated ER, PR, AR, and GR expression, using immunohistochemistry, in a cohort of 169 breast cancer patients and correlated these findings with clinical and pathological parameters. RESULTS: We found that AR is more frequently expressed and at higher levels in the ER+PR- subset compared to ER+PR+ tumors. There were no significant differences in GR expression between tumor subsets. Moreover, most luminal tumors also expressed either AR or GR and most basal tumors were also negative for AR and GR. CONCLUSION: These data suggest that targeting AR in ER+PR- tumors may represent a promising therapeutic alternative in hormonal refractory tumors.

Optimizing Diagnostic Accuracy of Fine Needle Aspiration Biopsy Calcitonin Measurements in Detecting Medullary Thyroid Carcinoma.

Background: The optimal cutoff value of calcitonin (Ctn) levels measured using an electrochemiluminescence immunoassay (ECLIA) obtained from the washout fluid of fine needle aspiration (FNA-Ctn) for the diagnosis of medullary thyroid carcinoma (MTC) is currently not established. We evaluated the diagnostic accuracy and clinical utility of FNA-Ctn for the diagnosis and location of MTC in patients with nodular or multinodular goiters. Methods: This was a case-control study nested on a prospective multicenter cohort of patients with nodular or multinodular goiter, normal or elevated serum Ctn, and thyroidectomy indications. Ctn and FNA-Ctn were measured using ECLIA methodology before surgery. From this nested cohort, MTC cases and controls (non-medullary pathology) were identified from the final pathological analysis. Cumulative incidence sampling of controls was randomly performed at a ratio of 1:2. Sensitivity, specificity, and area under the receiver operator curve (AUROC) were calculated for patients and the total number of thyroid nodules. Results: From 1272 patients included in the prospective cohort, 50 MTC cases and 105 controls were included. In this study, 286 thyroid nodules were evaluated (63 MTC and 223 non-MTCs). The median serum Ctn value was significantly higher in cases (525 pg/mL [interquartile range (IQR), 162.5-1.200]) than in controls (1.6 pg/mL [IQR, 0.5-5.6]; p < 0.001). The median FNA-Ctn value was significantly higher in MTC nodules (3.100 pg/mL [IQR, 450-45,200]) than in non-MTC nodules (0.5 pg/mL [IQR, 0.5-0.5]; p < 0.0001). In 11 MTC patients with multinodular goiter, the FNA-Ctn value was significantly higher in non-medullary nodules located in the same lobe where an MTC nodule was diagnosed (p = 0.0002). Overall, the FNA-Ctn AUROC was 0.99 [95% confidence interval, 0.98-1.0], and a threshold of ≥220 pg/mL showed 100% sensitivity and 98% specificity for MTC diagnosis. Conclusions: The use of FNA-Ctn measured by ECLIA showed adequate diagnostic accuracy for MTC diagnosis. Moreover, it may be clinically useful for localization in multinodular goiter when lobectomy is considered. Clinical Trial Registration: Clinicaltrials.gov NCT06067594.

Beneficial Effects of Mifepristone Treatment in Patients with Breast Cancer Selected by the Progesterone Receptor Isoform Ratio: Results from the MIPRA Trial.

PURPOSE: Preclinical data suggest that antiprogestins inhibit the growth of luminal breast carcinomas that express higher levels of progesterone receptor isoform A (PRA) than isoform B (PRB). Thus, we designed a presurgical window of opportunity trial to determine the therapeutic effects of mifepristone in patients with breast cancer, based on their high PRA/PRB isoform ratio (MIPRA; NCT02651844). PATIENTS AND METHODS: Twenty patients with luminal breast carcinomas with PRA/PRB > 1.5 (determined by Western blots), and PR ≥ 50%, naïve from previous treatment, were included for mifepristone treatment (200 mg/day orally; 14 days). Core needle biopsies and surgical samples were formalin fixed for IHC studies, while others were snap-frozen to perform RNA sequencing (RNA-seq), proteomics, and/or Western blot studies. Plasma mifepristone levels were determined using mass spectrometry. The primary endpoint was the comparison of Ki67 expression pretreatment and posttreatment. RESULTS: A 49.62% decrease in Ki67 staining was observed in all surgical specimens compared with baseline (P = 0.0003). Using the prespecified response parameter (30% relative reduction), we identified 14 of 20 responders. Mifepristone induced an increase in tumor-infiltrating lymphocytes; a decrease in hormone receptor and pSer118ER expression; and an increase in calregulin, p21, p15, and activated caspase 3 expression. RNA-seq and proteomic studies identified downregulated pathways related to cell proliferation and upregulated pathways related to immune bioprocesses and extracellular matrix remodeling. CONCLUSIONS: Our results support the use of mifepristone in patients with luminal breast cancer with high PRA/PRB ratios. The combined effects of mifepristone and estrogen receptor modulators warrant clinical evaluation to improve endocrine treatment responsiveness in these patients. See related commentary by Ronchi and Brisken, p. 833.

The tale of TILs in breast cancer: A report from The International Immuno-Oncology Biomarker Working Group.

The advent of immune-checkpoint inhibitors (ICI) in modern oncology has significantly improved survival in several cancer settings. A subgroup of women with breast cancer (BC) has immunogenic infiltration of lymphocytes with expression of programmed death-ligand 1 (PD-L1). These patients may potentially benefit from ICI targeting the programmed death 1 (PD-1)/PD-L1 signaling axis. The use of tumor-infiltrating lymphocytes (TILs) as predictive and prognostic biomarkers has been under intense examination. Emerging data suggest that TILs are associated with response to both cytotoxic treatments and immunotherapy, particularly for patients with triple-negative BC. In this review from The International Immuno-Oncology Biomarker Working Group, we discuss (a) the biological understanding of TILs, (b) their analytical and clinical validity and efforts toward the clinical utility in BC, and (c) the current status of PD-L1 and TIL testing across different continents, including experiences from low-to-middle-income countries, incorporating also the view of a patient advocate. This information will help set the stage for future approaches to optimize the understanding and clinical utilization of TIL analysis in patients with BC.

Biopsia radioquirúrgica asistida por radioscopia intraoperatoria. Descripción del método y nuestra experiencia en el Hospital Universitario Austral / Intraoperative radioscopy-assisted radiosurgical biopsy. Description of the method and our experience at the Austral University Hospital

Introducción: En la actualidad entre un 25 y 30% de los cánceres de mama se representan por lesiones no palpables. Es por eso que ha aumentado y se nos exige cada vez más en la detección de estas lesiones y posterior tratamiento de las mismas. Presentamos en este trabajo nuestra experiencia desde 2014 a 2020 de la realización de Biopsia radio quirúrgica guiada por radioscopia intraoperatoria. Objetivo: El objetivo de nuestro trabajo es evaluar si la BRQ asistida por radioscopia permitió mejorar ciertos parámetros, como la evaluación de márgenes quirúrgicos, tasas de retumorectomias, volumen de tejido resecado y tiempo quirúrgico empleado. Material y método: Se realizó un estudio observacional retrospectivo de tipo corte transversal, incluyendo las pacientes con lesiones mamarias no palpables a las cuales se les realizó punción biopsia y colocación de clip metálico, y que luego fueron sometidas a BRQ en el Centro Mamario del Hospital Universitario Austral entre noviembre de 2014 a noviembre de 2020. Resultados: Se incluyeron un total de 128 pacientes. En el 100% de las cirugías se logró la extracción del clip, colocado preoperatoriamente. No encontramos diferencias estadísticamente significativas, entre ambos grupos con respecto a la edad de las pacientes, tipo de cirugía, piezas obtenidas, márgenes quirúrgicos y necesidad de re operación. Sí se constató una diferencia estadísticamente significativa en cuanto al volumen total resecado, siendo esta menor en la técnica de BRQ con radioscopia, infiriendo un mejor resultado cosmético. Conclusiones: La biopsia radioquirúrgica asistida por radioscopia es un procedimiento sencillo que permite extirpar las lesiones no palpables de la mama, minimizando la probabilidad de fallo del procedimiento, y con menor volumen de tejido mamario resecado. Con la sistematización de la técnica, se podrían mejorar otros parámetros, inclusive los costos del procedimiento, lo cual creemos que da un gran beneficio en la práctica diaria para la resección de estas lesiones(AU)

Introduction: Currently, between 25 and 30% of breast cancers are represented by non-palpable lesions. That is why it has increased and we are increasingly required to detect these lesions and later treat them. In this study we present our experience from 2014 to 2020 of performing intraoperative fluoroscopy-guided radio-surgical biopsy. Objetive: The objective of our workis to evaluate whether radioscopy-assisted BRQ allowed to improve certain parameters, such as the evaluation of surgical margins, re-lumpectomy rates, volume of resected tissue, and surgical time used. Material and method: A retrospective cross-sectional observational study was carried out, including patients with non-palpable breast lesions who underwent a biopsy puncture and metal clip placement, and who then underwent BRQ at the Breast Center of the Austral University Hospital between November from 2014 to November 2020. Results: A total of 128 patients were included. In 100% of the surgeries, the clip was extracted, placed preoperatively. We did not find statistically significant differences between both groups with respect to the age of the patients, type of surgery, pieces obtained, surgical margins and need for reoperation. A statistically significant difference was found in terms of the total volume resected, this being less in the BRQ technique with fluoroscopy, inferring a better cosmetic result. The aesthetic result is very good. Conclusions: Radioscopy -assisted radio surgical biopsy is a simple procedure that allows the removal of non-palpable breast lesions, minimizing the probability of procedural failure, and with a smaller volume of resected breast tissue. With the systematization of the technique, other parameters could be improved, including the costs of the procedure, which we believe is of great benefit in daily practice for the resection of these lesions(AU)

Gastritis multifocal atrofica asociada a adenocarcinoma gástrico / Multifocal atrophic gastritis associated to gastric adenocarcinoma

Objetivo: Correlacionar la presencia de Gastritis Multifocal Atrofica con el adenocarcinoma gastrico. Se tomaron 46 piezas de gastrectomía de los cuales 34 eran hombres, el rango etario estuvo comprendido entre 35 y 83 años...