Karolina Hofman-Pyka1, Andrzej Witkoś1, Teresa Lisik1, Ewa Nowakowska-Zajdel1, 2
1Department of Clinical Oncology, Voivodal Specialist Hospital Number 4 in Bytom
2Department of Prophylaxis of Food-Depended Diseases, School of Public Health in Bytom, Medical University of Silesia in Katowice
Late recurrence of breast cancer in a patient with BRCA1 mutation and subsequent radical treatment for colorectal and endometrial cancer — a case report
ABSTRACT
Breast cancer is the most common malignancy in women. Hereditary predisposition is found in 5–10% women with breast cancer and most frequently depends on BRCA1 and BRCA2 mutations. In BRCA1 mutation carriers there is a 56–84% risk of breast cancer and a 36–63% risk of ovarian cancer, while in BRCA2 it is 45–85% and 10–27%, respectively. In both groups there is a 2–3-fold risk of other malignancies. We present a case of a BRCA1 mutation carrier with late relapse of breast cancer after radical treatment for two other malignancies (colorectal and endometrial cancer).
Key words: breast cancer, BRCA1/2 gene mutations, late relapse, colorectal cancer, endometrial cancer
Oncol Clin Pract 2016; 12, 1: 29–32
Introduction
Breast cancer (BC) is one of the most frequent malignancies worldwide (25% of all malignant diseases in female patients). In 2012 there were 1.7 million new cases and app. 0.5 million of deaths [1]. In Poland there were 16.850 cases of BC in women in the same year (23% of all new cases, standardised incidence ratio approximately 52 per 100,000 persons) and approximately 100 new cases in male patients. The risk factors include: early puberty and late menopause, late first termed pregnancy, nulliparity, life style (dietary factors, drugs, lack of physical activity), and genetic implications [2, 3]. Approximately 5–10% of patients indicate hereditary predispositions to BC, and most frequently this results from mutations of BRCA1 and BRCA2 genes (less commonly — TP53, PTEN, STK11, CHEK2, ATM, RAD51C, RAD50, PALB2, MRE11A, ATM, NBS1, CDH1, and BARD) [2, 4].
The BRCA1 gene is localised on the long arm of 17 (17q21) chromosome, and the BRCA2 gene on the long arm of 13 (13q12–13) chromosome. Mutations of the indicated genes lead to the creation of shortened protein product and the lack of its function, and subsequently to impairment of DNA repair (especially the rupture of both DNA threads), lessening of cell cycle control in G2/M phase, and disorders of cell divisions and apoptosis. Large size of these genes and heterogeneity of allele comprise the diagnostic challenge of temporary genetics and oncology. Molecular screening tests consist of detection of most common and reproducible mutations in a certain population, so-called founder mutations [3, 4]. The Polish population is characterised by high homogeneity of the carriage of BRCA gene mutations. Approximately 90% of detected abnormalities in BRCA1 and BRCA2 genes consist of three mutations (5382insC, C61G, and 4153delA). These mutations are inherited as autosomal dominant and are characterised by high penetration (10–30-fold higher risk of disease than in the general population) [4, 5].
The carriers of the BRCA1 gene mutations indicate approximately 56–84% risk of BC development and 36–62% risk of ovarian cancer. Research on the BRCA2 gene revealed increased risk of BC of up to 45–85%, and of ovarian cancer of up to 10–27%. Additionally, in both groups there is a 2–3-fold increased risk of development of other cancers (colon, endometrial and cervical, peritoneal, pancreatic, gastric, and prostate cancer, as well as leukaemia and lymphoma) [6–8].
Case report
In 1996 bifocal cancer of the left breast was detected in a 39-year-old woman. The patient underwent mastectomy (Patey’s type of amputation), and based on postoperative histological evaluation infiltrating cancer, partially necrotic (carcinoma infiltrans partim necroticans), Bloom II, stage pT1N0M0 was diagnosed. The patient was qualified to adjuvant chemotherapy according CMF protocol (cyclophosphamide, methotrexate, fluorouracil). Because of strong family history of cancer and young patient’s age genetic tests were recommended to evaluate any possible congenital genetic predisposition to ovarian and breast cancer; a mutation in BRCA1 was detected. Then the patient was actively followed-up in an oncology outpatient clinic, where in 2003 a 5-mm tumour of the right breast was revealed. Again, the patient was qualified to mastectomy (Patey’s type), and based on postoperative histological evaluation invasive intraductal cancer, partially comedus type (carcinoma intraductale, partim typus comedus invasivum) G2 was diagnosed. Results of molecular tests included no expression of oestrogen or progesterone receptors [ER(–)/PR(–)], no expression of human epidermal growth factor receptor 2 [HER2(–)], and high proliferation activity (Ki-67 45%). According to the low cancer stage (pT1aNOM0) in the patient without expression of either hormonal receptor, as well as HER2, adjuvant treatment was not introduced and further ambulatory follow-up was recommended.
In periodical computed tomography (CT) assessments of the chest performed since 2006, nodular pulmonary densities were observed with maximal size of 6 mm, but without any further growth dynamics. Ca125 levels were within the normal range. Due to suspicions of local disease recurrence twice within postoperative scare in right breast fine needle aspiration biopsy (BAC) has been performed in 2005 and repeatedly in 2006, excluding cancer histology. Patient complained of arthralgia, skin rash, mucous changes, and subfebrile states. Comprehensive rheumatological diagnostics revealed Sjögren’s syndrome with a component of polyarthritis and suspicion of systemic lupus erythematosus (SLE). Immunosuppressive therapy (corticosteroids, sulfasalazine) was introduced until recovery.
Control colonoscopy, performed in June 2013, identified a flat polyp with a diameter of 10 mm in rectum. Biopsy was performed and tissue samples examination detected focuses of adenocarcinoma (foci adenocarcinomatosi). In laboratory evaluations CEA levels were normal (3.09 ng/mL), CT scans of the abdomen and pelvis indicated enlarged heterogeneous uterus, further picture was normal, without features of cancer dissemination. The patient underwent partial rectal resection of the uterus, and postoperative histological examination revealed complete cancer resection (pT1a) without unequivocal confirmation of adenoma structure. Additional immunohistochemistry (IHC) examinations showed expression of CDX2 and CK7 as well as no reaction with mammoglobin and PAX 8, excluding cancer origin from the gastrointestinal tract.
Following surgery patient was referred for additional gynaecological diagnostics due to suspicion of endometrial cancer. In September 2013 total hysterectomy and adnexectomy was performed. Histological examination indicated endometrial adenocarcinoma, partially papillary (adenocarcinoma endometrioides partim papillare) G2. Stage pT1a was diagnosed and no adjuvant treatment was recommended.
In November 2013 local recurrence within the minor pelvis was suspected on standard imaging. Positron emission tomography (PET) exam confirmed the presence of metabolically active foci in the vaginal apex (standardised uptake value — SUV 5.06), mesorectum (SUV 2.06) and segment III of the right lung (SUV 0.91). CEA level was 3.3 ng/L. Core-needle biopsy (CNB) of perirectal lymph node was performed. Histological examination confirmed focuses of neoplastic dissemination (foci carcinomatosi disseminati). Anterior rectal resection was perfomed and postoperative specimen examination revealed a focus of cancer infiltration in fat tissue with a diameter of 2 cm. The diagnosis of metastatic adenocarcinoma (most likely of endometrial origin) was established. The patient received radiotherapy (RT) in the area of postoperative lodge with a total dose of 59.4 Gy/tumour and in the area of the lesser pelvis lymph nodes with a total dose of 45 Gy/tumour.
In May 2015 rapidly increasing CEA level was observed (372 ng/mL). The patient was in good general health condition (WHO 0) with no signs/symptoms and abnormalities in physical examination. PET scan revealed metastases in lungs, mediastinum, and bones. Based on biopsy of mediastinal lymph nodes performed during endobronchial ultrasonography (EBUS) non-small-cell cancer (carcinoma non-microcellulare) was diagnosed with suspicion of possible dissemination of breast cancer. To verify the diagnosis right thoracotomy was performed with resection of upper lung lobe lesions as well as hilar lymphadenectomy. Immunohistochemistry assays confirmed metastases of ductal breast carcinoma with partial mucinous differentiation [cells phenotype: CK7(+), CK20(+), E-catherin(+), ER(–), Pr(+), CEA(+), CDX2(+), mammoglobin(–), TTF1(–), WT1(–), p16+/–. The patient received first-line chemotherapy due to breast cancer dissemination based on liposomal doxorubicin and cyclophosphamide. The treatment is ongoing.
Discussion
Patients with BRCA1 gene mutation often suffer from “triple-negative” breast cancer (57%) with no expression of steroid receptors as well as negative HER2 status. Usually the prognosis in this group of patients is worse than in patients with hormone-dependent breast cancer, with more frequent metastases to visceral organs and central nervous system [9, 10]. The risk of recurrence of disease is the highest in the first 3 years after surgical treatment [9]. Furthermore, the presence of BRCA1/2 mutations is connected with higher risk of development of other cancers, and the most frequent among them is cancer of the second breast. In an analysis of 491 patients with family history of mutation in the BRCA gene Metcalfe et al. [11] showed that all patients with mutation in the BRCA1 or BRCA2 genes have higher risk of development of second breast cancer during 10-year follow-up after first breast cancer diagnosis (32% and 24.5%, respectively). In this analysis increasing risk correlated with the patient’s age at first diagnosis of breast cancer (31% and 23.5% for patients below and over 50 years of age, respectively). Menes et al. [12] confirmed the same relationship with mutation in BRCA1 gene and patients’ age. In breast cancer patients with mutation in BRCA1 gene and diagnosis made before 40 years of age the risk of development of second breast cancer during 10-year follow-up was 21% (11% for cancers diagnosed after four years of age). Nevertheless, the authors did not confirm such a connection with mutation in the BRCA2 gene. A meta-analysis performed by Molina-Montes et al. [13] indicated increasing of the risk during five years of follow-up by 15% and 9% for patients with mutations in BRCA1 and BRCA2 gene, respectively, and further risk increasing with time since first diagnosis (10-year risk, 27% and 19%, respectively). In patients without mutations the 5-year and 10-year risks were significantly lower (3% and 5%).
The relationship between mutated BRCA1/2 genes and higher risk of colon cancer is not unequivocal. This correlation was indicated in an analysis of 586 patients made by Kirchhoff et al. [14] and an analysis of 1422 patients made by Niell et al. [15]. In their report of a prospective analysis of 715 patients, Phelan et al. [16] indicated higher risk of colon cancer in patients below 50 years of age harbouring mutation in the BRCA1 gene. In older patients as well as those with mutation in the BRCA2 gene such a correlation was not revealed.
Beiner et al. [17] and Segev et al. [18] indicated higher risk of endometrial cancerin patients harbouring mutations in BRCA genes. This correlation was significantly disclosed in patients receiving adjuvant tamoxifen. Bruchim et al. [19] presented higher incidence of mutations in BRCA1/2 genes in patients with serous subtype endometrial cancer.
In Poland women with confirmed mutations in BRCA1/2 genes are included into a program aiming to decrease the number of deaths due to breast and ovarian cancer. In women aged from 25 to 60 years it is recommended that imaging examinations of the breasts be performed every 6 months — (mammography (MMG) and magnetic resonance (MR) are recommended, and — beginning at the age of 30–35 years — annual gynaecological examinations together with transvaginal ultrasound examination (USG), assessment of Ca125 serum levels, and cervical cytological examinations in three-year intervals [2, 4]. Due to increased risk of other cancers it is worth considering colonoscopy, especially in younger women with confirmed mutation in the BRCA1 gene.
Additionally, taking into consideration the higher risk of concomitantly present independent malignant diseases in patients with a family predisposition to breast and ovarian cancer, the histology of each particular neoplastic focus detected should be verified with IHC assays in order to make appropriate therapeutic decisions. Recurrence of disease 10 or 15 years after primary diagnosis, independently of mutations in BRCA1/2 genes, justifies the need for continuous observation in an oncology outpatient clinic. The presented case report indicates that oncological vigilance gives a chance of early detection of recurrence of disease and further cancers with the option for radical treatment and hence prolongation of overall survival.
Address for correspondence:
Lek. Karolina Hofman-Pyka
Oddział Onkologii Klinicznej
Wojewódzki Szpital Specjalistyczny nr 4 w Bytomiu
e-mail: hofman.pyka@gmail.com
Oncology in Clinical Practice
2016, Vol. 12, No. 1, 29–32
Translation: dr n. med. Dariusz Stencel
Copyright © 2016 Via Medica
ISSN 2450–1654
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