Extragenital malignant mixed mesodermal müllerian tumors (MT) are rare neoplasms with poor prognosis. Most of them affect women older than 60 years. We present here a case with primary peritoneal malignant mixed müllerian tumor occurring in a young woman who underwent previous hysterectomy and double oophorectomy secondary to a benign disease. We report on the clinical, pathological, and immunohistochemical features of this lesion, which was composed of a poorly differentiated epithelial component and multiple areas of chondromatous differentiation. Along with a brief review of previously reported literature about genital and extragenital MT, some concepts relevant to this case are discussed.
Background: Prosigna's ROR score was demonstrated as a strong predictor of response to NAC in a representative cohort of EBC patients including HR+/HER2- N0-N1 patients.1 Given that the ROR score is partially derived from the correlation of the tumor's expression profile to that of the four prototypical intrinsic subtypes, we determined the relative strength of the association between each subtype correlation and the likelihood of response to NAC. Methods: We analyzed 294 FFPE breast cancer samples from pts treated with NAC (anthracyclines and taxanes) in a multi-center Spanish cohort. The Prosigna Assay was performed on the NanoString nCounter® Dx Analysis System at HU Virgen de la Victoria de Málaga/CIMES-UMA. Pathologic complete response (pCR) was used as the primary endpoint for this study and was determined using the Miller and Payne scoring criteria. Results: Mean patient age in this population was 50 (±11yr). Apart from targeted therapy, all patients received a standard neoadjuvant treatment regimen consisting of 8-12 cycles of anthracyclines and taxanes. 58% of patients were HR+/HER2- while 24% were classified as HER2+ and 18% were TNBC patients. Of the 311 pts samples previously tested, subtype correlation data was available for 294. Overall subtype concordance between IHC and Prosigna was 72% (K=0.66). The overall pCR rate in this population was 24.9%. Prosigna subtype breakdown in the full study population was 60 Luminal A, 118 Luminal B, 69 HER2-enriched and 47 Basal-like with response rates of 7.2%, 7.2%, 46.2% and 57.4%, respectively. We found that in all study populations, subtype correlation was a strong predictor of response to NAC. Tumors with expression profiles that correlated well with the Luminal prototypical centroids were found to be largely unresponsive to NAC (Luminal A Odds ratio=0.074 per unit increase, p<0.0001; Luminal B Odds ratio=0.059 per unit increase, p<0.0001). Conversely, higher HER2E and Basal-like correlations were associated with increased probability of response (HER2E Odds ratio=11.2 per unit increase, p<0.0001; Basal-like Odds ratio=9.0 per unit increase, p<0.0001). Increased proliferation-score (p-score) was also associated with increased probability of response to NAC (Odds ratio=3.43 per unit increase, p<0.0001). Conclusions: In a representative cohort of breast cancer patients, both the magnitude of the subtype correlation to the prototypical centroids as well as p-score, as determined by the Prosigna Assay, were strong predictors of response to NAC. This data underlines the importance of molecular testing for optimal systemic therapy indications in EBC. 1Rodriguez B, Lavado Fernandez A, Ribelles N, et al. Prosigna (PAM50) to predict response to neoadjuvant chemotherapy (NAC) in HR+/HER2- early breast cancer (EBC) patients. J Clin Oncol 33, 2015 (suppl; abstr 11049). Citation Format: Chica Parrado R, Jiménez-Rodríguez B, Sánchez Rovira P, Álvarez M, Vicioso L, Fernandez AI, de Luque V, José Lozano M, Villar E, Zarcos I, Ramírez C, González-Hermoso C, Jeiranian A, Dowidar N, Schaper C, Buckingham W, Ferree S, Ribelles N, Rodrigo I, Prat AP, Alba E. Prosigna® subtype correlation is a strong predictor of response to neoadjuvant chemotherapy (NAC) in early breast cancer (EBC) study. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-07-15.
Progesterone receptor (PR) is currently used as a surrogate marker for functional estrogen receptor activity in breast cancer. Two PR isoforms have been described, PRB and PRA. PRA (94 kDa) is a truncated protein that lacks the first 164 amino acids of the NH2 terminal of PRB (115 kDa), making difficult the development of antibodies that discriminate PRA from PRB by standard immunohistochemistry (IHC). There are few studies describing the expression of PR isoforms in breast cancers. While there is a general consensus that PRA is the prevailing isoform expressed in breast cancer tissues as compared with normal mammary gland, there is controversial data regarding the association between their deregulated expression and endocrine response or aggressiveness. We are currently studying the expression of the PR isoform ratio in breast cancer samples obtained during surgical resection in order to test their antiprogestin responsiveness in tissue cultures. The study has been approved by the IRB (2012-028). Selected samples were studied by RNAseq and the data was used to analyze the PAM50 genes to predict risk of recurrence, and interestingly, almost all the genes related to proliferation were up-regulated in samples categorized as having higher levels of PRB than PRA, being also these patients those with a high risk of recurrence (May and Rojas et al., ASCO Annual Meeting, poster#11016, 2015). These observations are in agreement with data obtained in hormone resistant breast cancer xenografts with higher levels of PRB than PRA (Wargon and Riggio et al, International Journal of Cancer: 2680, 2015). The aim of this study is to evaluate a possible correlation between the PR isoform ratio, proliferation as evaluated by Ki67 or HER2 expression, and clinical outcome in selected breast cancer samples. Ki67 was evaluated by IHC using standard protocols in 80 PR+ samples. The PRA/PRB ratio was also evaluated in nuclear extracts, performed from frozen tissue, from the same patients, by Western Blot. A negative correlation was observed between the Ki67 score and the log2 value of the PRA/PRB ratio (Spearman R:-0.3418; p< 0.0029). Samples were considered PRA+ if PRA/PRB ≥ 1.2 and PRB+, if PRA/PRB ≤ 0.83. Seven out of 62 PRA+ (11.29%), and 7 out of 35 (20%) of PRB+ samples were HER2+. The differences between both groups, although not significant, correlate directly with the Ki67 evaluation. The results of this ongoing project lend support to the hypothesis that the ratio of PRA/PRB is associated with prognosis and highlight the role of PR as key players regulating breast cancer growth. Citation Format: Gass HD, May M, Rojas P, Abba M, Sequeira G, Martinez Vazquez P, Gonzalez PL, Elía A, Alvarez MM, Molinolo A, Lanari CL. Breast cancer recurrence risk: A role for the progesterone receptor isoforms. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-09-13.
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