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Synchronous Ovarian and Breast Cancers with a Novel Variant in BRCA2 Gene: A Case Report

Synchronous Ovarian and Breast Cancers with a Novel Variant in BRCA2 Gene: A Case Report Hindawi Case Reports in Oncological Medicine Volume 2019, Article ID 6958952, 5 pages https://doi.org/10.1155/2019/6958952 Case Report Synchronous Ovarian and Breast Cancers with a Novel Variant in BRCA2 Gene: A Case Report 1,2 2 3 Néstor Llinás-Quintero , Eduardo Cabrera-Florez, Gustavo Mendoza-Fandiño, 4 5 2 Gustavo Matute-Turizo, Elsa M. Vasquez-Trespalacios , and Luis J. Gallón-Villegas Breast Surgery Fellowship Program, School of Medicine, CES University, Medellín, Colombia School of Medicine, CES University, Medellín, Colombia Departament of Public Health, School of Medicine, CES University, Medellín, Colombia Pathology and Cytology Laboratory LLC (LAPACI), Medellín, Colombia Epidemiology Department, School of Medicine, CES University, Medellín, Colombia Correspondence should be addressed to Néstor Llinás-Quintero; nllinas71@gmail.com Received 2 March 2018; Revised 10 September 2018; Accepted 9 December 2018; Published 6 January 2019 Academic Editor: Su Ming Tan Copyright © 2019 Néstor Llinás-Quintero et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. We report a case of a 52-year-old female with a family history of pancreatic and colon cancers who presented with a right breast mass positive for high-grade medullar carcinoma with triple-negative biomolecular profile. Further workup was performed finding a left ovarian mass. The patient underwent laparotomy performing optimal cytoreduction on bilateral ovarian tumors; the pathology and immunohistochemistry confirmed bilateral ovary adenocarcinoma with positive peritoneal malignancy. Due to her synchronic breast and ovarian cancers, a genetic profile was performed detecting a new pathogenic variant in the BRCA2 gene: c.3606_3607del (p.Ser1203Cysfs). She was given chemotherapy with carboplatin and paclitaxel obtaining complete clinical response. Regarding her breast cancer, she had a right modified radical mastectomy and prophylactic left mastectomy obtaining complete clinical response. This case presents with an unusual subtype and difficult histologic diagnosis of a synchronic medullar breast cancer and ovary carcinoma associated with a new mutation of the BRCA2 gene. 1. Case Report We evaluated metastasis by chest X-rays and bone scintigraphy; no evidence of metastasis was identified. Abdominal ultrasound did not report liver lesions. A left A 52-year-old patient presented with a tumor on her right ovary lesion was identified measuring 105 × 101 × 80 mm. breast. Routine mammography classified it as BIRADS-0. A The patient underwent exploratory laparotomy, which mammary ultrasound confirmed a complex cystic lesion in allowed the identification and resection of bilateral ovarian the upper quadrants of the right breast. Histopathological analysis of a biopsy of the tumor showed a poorly differen- tumors. During the laparoscopic resection, analysis of the left ovary indicated an epithelial malignant tumor, consistent tiated carcinoma with necrosis. An incisional biopsy of the with breast cancer metastasis. Bilateral ovarian involvement breast tumor was performed and histopathology analysis by poorly differentiated adenocarcinoma was reported. Peri- reported it as a nuclear grade-3 medullary carcinoma. Pathol- toneal cavity cytology identified additional malignancies, ogy and immunohistochemistry of the lesion (60 × 40 mm) revealed an estrogen receptor negative (ER-), progesterone which by immunohistochemical studies were positive for the expression of WT1 and CA125 proteins suggesting an receptor negative (PR-), HER2 negative (HER2-), and ovarian origin. The ovarian lesion was classified as serous Ki67 index of 20% mass (Figure 1), which led to the cystadenocarcinoma. The patient underwent ovarian cancer diagnosis of adenocarcinoma stage IIB (pT3N0M0) of the staging surgery; uterine surgical pathology, remnant annexes, right breast. 2 Case Reports in Oncological Medicine (a) (b) (c) (d) (e) (f) Figure 1: Immunohistochemical analysis of the breast lesion. (a) H&E 200x: central necrosis is observed, peripheral neoplastic cells with eosinophilic cytoplasm, large nuclei, prominent nucleoli, atypical mitosis, and mononuclear infiltrates. Representative micrographs (at 400x) are shown for immunohistochemical analysis of (b) leukocyte common antigen (LCA), showing positive expression in peritumoral lymphocytes. (c) Ki67 expression is detected in 60% of cancer cells; lack of expression of (d) estrogen receptor (ER), (e) progesterone receptor (PR), and (f) HER2. appendix, and omentum were negative for malignancy, 2. Discussion obturator nodes were negative (0/11), and diaphragmatic cytology and parietocolic leakage were also negative. The Triple-negative breast cancer (TNBC) and BRCA1/2-mu- final diagnosis was high-risk synchronous cancer, stage IIB tated breast cancers have been previously reported to exhibit triple-negative breast cancer, and stage IIIA ovarian cancer. sensitivity to platinum-based chemotherapy [1]. Thus, estab- The patient received adjuvant systemic therapy to treat lishing BRACA1/2 status may be useful to provide a tailored the ovarian cancer and neoadjuvant therapy to treat the chemotherapeutic regimen. The identification of patients at locally advanced breast cancer. The regimen was carboplatin risk of being a carrier of BRCA1/2 mutation is relevant to AUC5+paclitaxel 175 mg/m day, every 21 days × 6 cycles, hereditary cancer. BRCA1/2 mutation carriers are at high well tolerated, and exhibited complete clinical response. risk of breast cancer (RR > 10), similar to that observed in Genetic testing for BRCA1 or BRCA2 mutations (Myriad patients with a history of chest radiotherapy (usually lym- phatic cancer, before 30 years old) [2, 3], breast surgery, Genetics) reported a BRCA2 deleterious mutation: c.3606_ 3607del (p.Ser1203Cysfs) (Figure 2). The patient underwent systemic therapy, and other prophylactic interventions [4]. bilateral mastectomy and axillary lymph node dissection. Furthermore, when designing the strategy and therapeu- The final surgical pathology report indicated no residual tic approach for BRCA1/2 mutation carriers, the possibility disease, including 14 axillary ganglia, and a complete patho- of encountering synchronous and/or metachronous disease logical response (ypT0N0M0). Coadjuvant radiotherapy was must be taken into consideration. However, when diagnosing of 5000 cGy. Clinical follow-up after 33 months since diagno- synchronous disease, establishing whether it is a primary sis revealed no evidence of recurrent lesions and the patient ovarian cancer or a breast cancer metastasis to the ovary reported her life quality as good. may be challenging to determine. The additional possibility Regarding the family history, a sister presents the same of it being a metastatic ovarian cancer to the breast is seldom mutation in BRCA2: c.3606_3607del (p.Ser1203Cysfs). To found in the literature, and up to December 2015, only 110 our knowledge, their mother died with pancreatic cancer cases have been reported [5, 6]. While criteria used to identify and the father was diagnosed with colon cancer. Family metastatic carcinomas—and differentiate them from primary members are currently undergoing additional genetic tests. tumors—are mainly based on clinicopathologic findings, loss 6503 del TT 6252 ins G 6076 del GTTA 5844 del5 3606-3607 del (Ser1203Cys)fs 3034 del ACAA W31X Case Reports in Oncological Medicine 3 50 kb hg38 32,310,000 32,330,000 32,350,000 32,370,000 32,390,000 32,410,000 BRCA2 Exons 3 10 11 27 Figure 2: BRCA2 pathogenic variant: c.3606_3607del (p.Ser1203Cysfs). of heterozygosity (LOH) and mutational analysis may a specific standard of care protocol for the treatment of med- provide useful additional information, since prognosis and ullary carcinoma. Nonetheless, the NCCN provides clinical therapy of those two entities are different [7]. Furthermore, guidelines for the treatment of medullary carcinomas, which breast cancer metastasis to the ovaries with a prevalence from are similar to those established for other infiltrating ductal 10 to 30% is associated with BRCA1/2 mutation carriers, carcinomas of comparable size, grade, and LN status. which have worse prognosis, and is usually diagnosed during Additionally, medullary breast cancer has also been shown autopsy, prophylactic or therapeutic oophorectomies, and as to have a comparable metastatic ability to that of other incidental findings during routine surgery [8]. To date, met- high-grade carcinomas. Therefore, our patient was treated astatic breast cancer is generally identified histologically by with standard-of-care combination therapy for serous ovar- the positive expression of gross cystic disease fluid protein ian cancer (carboplatin+paclitaxel), as well as neoadjuvant 15 (GCDFP15), mammaglobin, and GATA3 and by the lack therapy for BRCA2 mutation carrier TNBC patients of expression of PAX8, CA125, and WT1. However, this is [13, 14]. While there is currently no standard of care in the not always the case, since within the TNBC, the basal subtype neoadjuvant setting for TNBC, and even to a lesser extent exhibits low expression of GCDFP15 (11.9%) and mamma- for BRCA1/2 mutation carrier breast cancer patients, several studies have reported the sensitivity of these tumors to globin (21.4%) [9]. Positive expression of CA125 and WT1 in metastatic breast cancer has also been reported [10]. platinum-based chemotherapy. The CALGB/Alliance 40603 Contrary to metastatic breast cancer, serous ovarian carci- and GeparSixto studies reported a pathological complete noma shows positive expression of PAX8, CA125, and response (pCR) and an improved disease-free survival WT1 and lacks expression of (GCDFP15), mammaglobin, (DSF) for TNBC patients receiving carboplatin + standard of care in the neoadjuvant setting. Analysis of BRCA1/2 and GATA3. On the other hand, primary endometrioid ovar- ian cancer is usually identified by positive expression of CK7, mutation carriers in those same studies showed no significant estrogen receptor (ER), CA125, and PAX8, while lacking effect in pCR (52% and 4.7%, respectively), and while DFS expression of CK20, CEA, and CDX2 [9–12]. was 85%, a greater toxicity was also reported for these Our patient was diagnosed with high-risk synchronous patients [15, 16]. Preliminary results from a third phase II study reported that the addition of nab-paclitaxel to carbo- cancer: stage IIB TNBC and stage IIIA ovarian cancer. Immunohistochemical analysis in the ovarian tissue showed platin led to a pCR of 53% [17]. Anthracycline-based therapy positive expression of CA125 and WT1. Because medullary is considerably toxic, thus—aiming to reduce toxicity—other carcinoma is uncommon, difficult to diagnose, and has anthracycline-free regimens have also been studied. A study significant interobserver variability, the National Compre- of 190 stage I-III TNBC revealed that patients (including BRCA1/2 germline mutation carriers) were treated in the hensive Care Network (NCCN) currently does not include 4 Case Reports in Oncological Medicine neoadjuvant setting with carboplatin (AUC 6)+docetaxel Conflicts of Interest (75 mg/m ), every 21 days, for 6 cycles. In that study, 16% The authors declare that they have no conflicts of interest. of the patients were BRCA1/2 germline mutation carriers and exhibited a pCR of 59%, comparable to that observed Acknowledgments by adding carboplatin to the anthracycline-taxane regimen [18]. Similarly, the phase II BSI-201 study (Telli et al.) Authors warmly thank CES University and Clinica Vida for showed that BRCA1/2 germline mutation carrier TNBC their support to this project. patients exhibited a pCR of 56% when treated with gemci- tabine, carboplatin, and iniparib (GCI), comparable to that References reported for TNBC patients receiving carboplatin+pacli- taxel in the neoadjuvant setting [19–21]. The I-SPY2 study [1] A. Dilawari, J. Cangiarella, J. Smith, A. Huang, A. Downey, and found a pCR of 52% in TNBC patients treated with F. Muggia, “Co-existence of breast and ovarian cancers in carboplatin/veliparib in combination with paclitaxel and BRCA germ-line mutation carriers,” ecancermedicalscience, anthracycline-based chemotherapy [22]. Finally, additional vol. 3, p. 109, 2008. studies have reported a pCR ranging from 90 to 100% using [2] M. María Eugenia Bravo, M. Octvio Peralta, V. Paulina Neira, cisplatin as single neoadjuvant agent for BRACA1 mutation and G. Laura Itriago, “Prevención y seguimiento del cáncer de carrier TNBC patients [23–25]. While carboplatin+taxane mama, según categorización de factores de riesgo y nivel de therapy in the neoadjuvant setting remains to be fully atención,” Revista Médica Clínica Las Condes, vol. 24, no. 4, demonstrated in order to be implemented as standard of pp. 578–587, 2013. care for TNBC patients, it may be a valid option to [3] J. E. Garber and M. Golshan, “Contralateral breast cancer in improve the pCR rates and DFS in those patients carrying BRCA1/BRCA2 mutation carriers: the story of the other side,” Journal of clinical oncology, vol. 27, no. 35, pp. 5862–5864, BRCA mutations. Thus, the search for BRCA1/2 pathogenic variants asso- [4] M. Gnant, N. Harbeck, and C. Thomssen, “St. Gallen/Vienna ciated with breast cancer is of clinical significance for the 2017: a brief summary of the consensus discussion about esca- individual patient, as well as for the patient’s relatives. In this lation and de-escalation of primary breast cancer treatment,” case report, we have identified the pathogenic BRCA2 variant Breast Care, vol. 12, no. 2, pp. 102–107, 2017. (c.3606_3607del (p.Ser1203Cysfs)), which—to our knowl- [5] R. L. Klein, A. R. Brown, C. M. Gomez-Castro et al., “Ovarian edge—has not been previously reported. The genetic screen- cancer metastatic to the breast presenting as inflammatory ing of her relatives is an ongoing study at our institution. breast cancer: a case report and literature review,” Journal of Medullary breast carcinomas (MBC) share specific genomic Cancer, vol. 1, pp. 27–31, 2010. characteristics. Transcriptomic profiles revealed that MBC [6] C. B. Tempfer, N. El Fizazi, H. Ergonenc, and W. Solass, differ from non-MBC with 92 genes overexpressed and 154 “Metastasis of ovarian cancer to the breast: a report of two genes underexpressed in MBC [26]. Differences in molecular cases and a review of the literature,” Oncology Letters, vol. 11, characteristics between MBC and invasive ductal tumors no. 6, pp. 4008–4012, 2016. with a basal-like phenotype may account for the relative [7] J. Prat, “Ovarian carcinomas, including secondary tumors: favorable outcome for MBC [27]. MBC have been reported diagnostically challenging areas,” Modern pathology, vol. 18, more frequently in Afro-American patients. Liao et al., in pp. S99–111, 2005. their multivariate analysis, taking infiltrating ductal carci- [8] P. Chen, W. M. Hu, P. H. Wang, and J. H. Suen, “Recurrent noma as a reference, found that patients with medullary or breast cancer presents as a single solid ovarian mass and asci- apocrine carcinoma had excellent prognosis and that patients tes,” Taiwanese journal of obstetrics & gynecology, vol. 45, with metaplastic or mixed lobular-ductal carcinoma had no. 4, pp. 356–359, 2006. poor survival outcomes [28]. With regard to clinical charac- [9] M.-H. Luo, Y.-H. Huang, Y.-B. Ni et al., “Expression of mam- teristics of MBC, some studies have reported a lower mean maglobin and gross cystic disease fluid protein-15 in breast carcinomas,” Human Pathology, vol. 44, no. 7, pp. 1241– age in MBC patients and mixed ductal-lobular compared 1250, 2013. with other TNBC subtypes. Lymph node status does not [10] L. I. Xiang and B. Kong, “PAX8 is a novel marker for differen- show statistical differences according to the histological tiating between various types of tumor, particularly ovarian subtype, but this may be due to small sample sizes [29]; epithelial carcinomas (review),” Oncology Letters, vol. 5, MBC had more limited stage and smaller tumors at presenta- no. 3, pp. 735–738, 2013. tion in a study assessing the histologic heterogeneity of [11] H. Liu, J. Shi, M. L. Wilkerson, and F. Lin, “Immunohisto- triple-negative breast cancer [30]. Considering local invasion, chemical evaluation of GATA3 expression in tumors and MBC seem to have a less aggressive manner compared to normal tissues a useful immunomarker for breast and invasive ductal carcinoma [31]. Overall survival of MBC urothelial carcinomas,” American Journal of Clinical Pathol- patients was higher when compared to that of invasive ductal ogy, vol. 138, no. 1, pp. 57–64, 2012. carcinoma patients [32, 33]. Zangouri et al. found a signifi- [12] C. Amalinei, R. Balan, E. Crauciuc, and O. Toma, “Synchro- cant statistical difference between invasive ductal carcinoma nous, metachronous and metastatic tumors of the upper and MBC (92.8% vs. 98.1%, P =0 004) and also with the female genital tract,” in Analele Ştiinţifice Ale Universităţii 5-year overall survival rate (86.3% vs. 94.2%, P =0 008) Alexandru Ioan Cuza din Iași, Sectiunea II A: Genetica si [31]. 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He, and in breast cancer,” Current Oncology, vol. 25, p. 151, 2018. S.-G. Wu, “The clinicopathological features and survival out- [15] C. Fontanella and F. Puglisi, “Translational and clinical comes of different histological subtypes in triple-negative research highlights from the 38th San Antonio Breast Cancer breast cancer,” Journal of Cancer, vol. 9, no. 2, pp. 296–303, Symposium,” Future oncology, vol. 12, no. 8, pp. 1005–1008, [29] G. Dreyer, T. Vandorpe, A. Smeets et al., “Triple negative [16] G. von Minckwitz, S. Loibl, A. Schneeweiss et al., “Abstract breast cancer: clinical characteristics in the different histologi- S2-04: early survival analysis of the randomized phase II trial cal subtypes,” The Breast, vol. 22, no. 5, pp. 761–766, 2013. investigating the addition of carboplatin to neoadjuvant [30] M. N. Mills, G. Q. Yang, D. E. 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Yu et al., “Pathologic complete response rates in triple-negative, HER2-positive, and hormone receptor-positive breast cancers after anthracycline-free neo- adjuvant chemotherapy with carboplatin and paclitaxel with or without trastuzumab,” Breast, vol. 24, no. 1, pp. 18–23, [21] P. Zhang, Y. Yin, H. Mo et al., “Better pathologic complete response and relapse-free survival after carboplatin plus pacli- taxel compared with epirubicin plus paclitaxel as neoadjuvant chemotherapy for locally advanced triple-negative breast cancer: a randomized phase 2 trial,” Oncotarget, vol. 7, no. 37, pp. 60647–60656, 2016. [22] C. Printz, “I-SPY2 trial yields first results on combination therapy for triple-negative breast cancer,” Cancer, vol. 120, no. 6, p. 773, 2014. [23] T. Byrski, T. Huzarski, R. Dent et al., “Response to neoadju- vant therapy with cisplatin in BRCA1-positive breast cancer patients,” Breast Cancer Research and Treatment, vol. 115, no. 2, pp. 359–363, 2009. [24] T. Byrski, J. 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Abstract

Hindawi Case Reports in Oncological Medicine Volume 2019, Article ID 6958952, 5 pages https://doi.org/10.1155/2019/6958952 Case Report Synchronous Ovarian and Breast Cancers with a Novel Variant in BRCA2 Gene: A Case Report 1,2 2 3 Néstor Llinás-Quintero , Eduardo Cabrera-Florez, Gustavo Mendoza-Fandiño, 4 5 2 Gustavo Matute-Turizo, Elsa M. Vasquez-Trespalacios , and Luis J. Gallón-Villegas Breast Surgery Fellowship Program, School of Medicine, CES University, Medellín, Colombia School of Medicine, CES University, Medellín, Colombia Departament of Public Health, School of Medicine, CES University, Medellín, Colombia Pathology and Cytology Laboratory LLC (LAPACI), Medellín, Colombia Epidemiology Department, School of Medicine, CES University, Medellín, Colombia Correspondence should be addressed to Néstor Llinás-Quintero; nllinas71@gmail.com Received 2 March 2018; Revised 10 September 2018; Accepted 9 December 2018; Published 6 January 2019 Academic Editor: Su Ming Tan Copyright © 2019 Néstor Llinás-Quintero et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. We report a case of a 52-year-old female with a family history of pancreatic and colon cancers who presented with a right breast mass positive for high-grade medullar carcinoma with triple-negative biomolecular profile. Further workup was performed finding a left ovarian mass. The patient underwent laparotomy performing optimal cytoreduction on bilateral ovarian tumors; the pathology and immunohistochemistry confirmed bilateral ovary adenocarcinoma with positive peritoneal malignancy. Due to her synchronic breast and ovarian cancers, a genetic profile was performed detecting a new pathogenic variant in the BRCA2 gene: c.3606_3607del (p.Ser1203Cysfs). She was given chemotherapy with carboplatin and paclitaxel obtaining complete clinical response. Regarding her breast cancer, she had a right modified radical mastectomy and prophylactic left mastectomy obtaining complete clinical response. This case presents with an unusual subtype and difficult histologic diagnosis of a synchronic medullar breast cancer and ovary carcinoma associated with a new mutation of the BRCA2 gene. 1. Case Report We evaluated metastasis by chest X-rays and bone scintigraphy; no evidence of metastasis was identified. Abdominal ultrasound did not report liver lesions. A left A 52-year-old patient presented with a tumor on her right ovary lesion was identified measuring 105 × 101 × 80 mm. breast. Routine mammography classified it as BIRADS-0. A The patient underwent exploratory laparotomy, which mammary ultrasound confirmed a complex cystic lesion in allowed the identification and resection of bilateral ovarian the upper quadrants of the right breast. Histopathological analysis of a biopsy of the tumor showed a poorly differen- tumors. During the laparoscopic resection, analysis of the left ovary indicated an epithelial malignant tumor, consistent tiated carcinoma with necrosis. An incisional biopsy of the with breast cancer metastasis. Bilateral ovarian involvement breast tumor was performed and histopathology analysis by poorly differentiated adenocarcinoma was reported. Peri- reported it as a nuclear grade-3 medullary carcinoma. Pathol- toneal cavity cytology identified additional malignancies, ogy and immunohistochemistry of the lesion (60 × 40 mm) revealed an estrogen receptor negative (ER-), progesterone which by immunohistochemical studies were positive for the expression of WT1 and CA125 proteins suggesting an receptor negative (PR-), HER2 negative (HER2-), and ovarian origin. The ovarian lesion was classified as serous Ki67 index of 20% mass (Figure 1), which led to the cystadenocarcinoma. The patient underwent ovarian cancer diagnosis of adenocarcinoma stage IIB (pT3N0M0) of the staging surgery; uterine surgical pathology, remnant annexes, right breast. 2 Case Reports in Oncological Medicine (a) (b) (c) (d) (e) (f) Figure 1: Immunohistochemical analysis of the breast lesion. (a) H&E 200x: central necrosis is observed, peripheral neoplastic cells with eosinophilic cytoplasm, large nuclei, prominent nucleoli, atypical mitosis, and mononuclear infiltrates. Representative micrographs (at 400x) are shown for immunohistochemical analysis of (b) leukocyte common antigen (LCA), showing positive expression in peritumoral lymphocytes. (c) Ki67 expression is detected in 60% of cancer cells; lack of expression of (d) estrogen receptor (ER), (e) progesterone receptor (PR), and (f) HER2. appendix, and omentum were negative for malignancy, 2. Discussion obturator nodes were negative (0/11), and diaphragmatic cytology and parietocolic leakage were also negative. The Triple-negative breast cancer (TNBC) and BRCA1/2-mu- final diagnosis was high-risk synchronous cancer, stage IIB tated breast cancers have been previously reported to exhibit triple-negative breast cancer, and stage IIIA ovarian cancer. sensitivity to platinum-based chemotherapy [1]. Thus, estab- The patient received adjuvant systemic therapy to treat lishing BRACA1/2 status may be useful to provide a tailored the ovarian cancer and neoadjuvant therapy to treat the chemotherapeutic regimen. The identification of patients at locally advanced breast cancer. The regimen was carboplatin risk of being a carrier of BRCA1/2 mutation is relevant to AUC5+paclitaxel 175 mg/m day, every 21 days × 6 cycles, hereditary cancer. BRCA1/2 mutation carriers are at high well tolerated, and exhibited complete clinical response. risk of breast cancer (RR > 10), similar to that observed in Genetic testing for BRCA1 or BRCA2 mutations (Myriad patients with a history of chest radiotherapy (usually lym- phatic cancer, before 30 years old) [2, 3], breast surgery, Genetics) reported a BRCA2 deleterious mutation: c.3606_ 3607del (p.Ser1203Cysfs) (Figure 2). The patient underwent systemic therapy, and other prophylactic interventions [4]. bilateral mastectomy and axillary lymph node dissection. Furthermore, when designing the strategy and therapeu- The final surgical pathology report indicated no residual tic approach for BRCA1/2 mutation carriers, the possibility disease, including 14 axillary ganglia, and a complete patho- of encountering synchronous and/or metachronous disease logical response (ypT0N0M0). Coadjuvant radiotherapy was must be taken into consideration. However, when diagnosing of 5000 cGy. Clinical follow-up after 33 months since diagno- synchronous disease, establishing whether it is a primary sis revealed no evidence of recurrent lesions and the patient ovarian cancer or a breast cancer metastasis to the ovary reported her life quality as good. may be challenging to determine. The additional possibility Regarding the family history, a sister presents the same of it being a metastatic ovarian cancer to the breast is seldom mutation in BRCA2: c.3606_3607del (p.Ser1203Cysfs). To found in the literature, and up to December 2015, only 110 our knowledge, their mother died with pancreatic cancer cases have been reported [5, 6]. While criteria used to identify and the father was diagnosed with colon cancer. Family metastatic carcinomas—and differentiate them from primary members are currently undergoing additional genetic tests. tumors—are mainly based on clinicopathologic findings, loss 6503 del TT 6252 ins G 6076 del GTTA 5844 del5 3606-3607 del (Ser1203Cys)fs 3034 del ACAA W31X Case Reports in Oncological Medicine 3 50 kb hg38 32,310,000 32,330,000 32,350,000 32,370,000 32,390,000 32,410,000 BRCA2 Exons 3 10 11 27 Figure 2: BRCA2 pathogenic variant: c.3606_3607del (p.Ser1203Cysfs). of heterozygosity (LOH) and mutational analysis may a specific standard of care protocol for the treatment of med- provide useful additional information, since prognosis and ullary carcinoma. Nonetheless, the NCCN provides clinical therapy of those two entities are different [7]. Furthermore, guidelines for the treatment of medullary carcinomas, which breast cancer metastasis to the ovaries with a prevalence from are similar to those established for other infiltrating ductal 10 to 30% is associated with BRCA1/2 mutation carriers, carcinomas of comparable size, grade, and LN status. which have worse prognosis, and is usually diagnosed during Additionally, medullary breast cancer has also been shown autopsy, prophylactic or therapeutic oophorectomies, and as to have a comparable metastatic ability to that of other incidental findings during routine surgery [8]. To date, met- high-grade carcinomas. Therefore, our patient was treated astatic breast cancer is generally identified histologically by with standard-of-care combination therapy for serous ovar- the positive expression of gross cystic disease fluid protein ian cancer (carboplatin+paclitaxel), as well as neoadjuvant 15 (GCDFP15), mammaglobin, and GATA3 and by the lack therapy for BRCA2 mutation carrier TNBC patients of expression of PAX8, CA125, and WT1. However, this is [13, 14]. While there is currently no standard of care in the not always the case, since within the TNBC, the basal subtype neoadjuvant setting for TNBC, and even to a lesser extent exhibits low expression of GCDFP15 (11.9%) and mamma- for BRCA1/2 mutation carrier breast cancer patients, several studies have reported the sensitivity of these tumors to globin (21.4%) [9]. Positive expression of CA125 and WT1 in metastatic breast cancer has also been reported [10]. platinum-based chemotherapy. The CALGB/Alliance 40603 Contrary to metastatic breast cancer, serous ovarian carci- and GeparSixto studies reported a pathological complete noma shows positive expression of PAX8, CA125, and response (pCR) and an improved disease-free survival WT1 and lacks expression of (GCDFP15), mammaglobin, (DSF) for TNBC patients receiving carboplatin + standard of care in the neoadjuvant setting. Analysis of BRCA1/2 and GATA3. On the other hand, primary endometrioid ovar- ian cancer is usually identified by positive expression of CK7, mutation carriers in those same studies showed no significant estrogen receptor (ER), CA125, and PAX8, while lacking effect in pCR (52% and 4.7%, respectively), and while DFS expression of CK20, CEA, and CDX2 [9–12]. was 85%, a greater toxicity was also reported for these Our patient was diagnosed with high-risk synchronous patients [15, 16]. Preliminary results from a third phase II study reported that the addition of nab-paclitaxel to carbo- cancer: stage IIB TNBC and stage IIIA ovarian cancer. Immunohistochemical analysis in the ovarian tissue showed platin led to a pCR of 53% [17]. Anthracycline-based therapy positive expression of CA125 and WT1. Because medullary is considerably toxic, thus—aiming to reduce toxicity—other carcinoma is uncommon, difficult to diagnose, and has anthracycline-free regimens have also been studied. A study significant interobserver variability, the National Compre- of 190 stage I-III TNBC revealed that patients (including BRCA1/2 germline mutation carriers) were treated in the hensive Care Network (NCCN) currently does not include 4 Case Reports in Oncological Medicine neoadjuvant setting with carboplatin (AUC 6)+docetaxel Conflicts of Interest (75 mg/m ), every 21 days, for 6 cycles. In that study, 16% The authors declare that they have no conflicts of interest. of the patients were BRCA1/2 germline mutation carriers and exhibited a pCR of 59%, comparable to that observed Acknowledgments by adding carboplatin to the anthracycline-taxane regimen [18]. Similarly, the phase II BSI-201 study (Telli et al.) Authors warmly thank CES University and Clinica Vida for showed that BRCA1/2 germline mutation carrier TNBC their support to this project. patients exhibited a pCR of 56% when treated with gemci- tabine, carboplatin, and iniparib (GCI), comparable to that References reported for TNBC patients receiving carboplatin+pacli- taxel in the neoadjuvant setting [19–21]. The I-SPY2 study [1] A. Dilawari, J. Cangiarella, J. Smith, A. Huang, A. Downey, and found a pCR of 52% in TNBC patients treated with F. 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