Abstract PS7-74: Associations and spectrum of genetic mutations in younger patients with breast carcinoma and additional malignancies
Authors: Agarwal Indu , Finkelman Brian , Blanco Luis Z. , Behdad Amir , Siziopikou Kalliopi 
Published: February 2021

Background: The development of cancer is understood to be a series of molecular events causing uncontrollable cell growth and malignant behavior. Primary breast carcinoma is associated with a number of molecular alterations that may also be implicated in the molecular deregulation underlying other malignancies. In addition, underlying germline genetic mutations have been clearly associated with the development of breast carcinoma (BC) in young patients. Increased risks for the development of additional malignancies following or preceding breast cancer have been reported, however, specific associations and genetic mutations remain unclear, especially in young patients.Materials and methods: Our patient cohort consisted of young women (&lt;!–=40 years of age) at our institution who were diagnosed with BC between May 2009 to May 2018. Retrospective review of electronic medical records was performed in order to identify the occurrence of a second neoplasm either before or after a BC diagnosis and germline genetic alterations were recorded.Results: 13 out of 437 young women were diagnosed with either a second malignancy or high-grade dysplasia. The clinico-pathologic characteristics of these patients are summarized in the Table 1. There was almost an equal distribution of these neoplasms occurring either before or after the diagnosis of BC. 6 tumors were diagnosed 10 months to 7 years after the diagnosis of BC, whereas 5 tumors diagnosed 1 month to 20 years earlier. Interestingly, only 2 cases were concurrently diagnosed and both of these were malignant phyllodes tumors of the breast.On studying the pathologic characteristics of the breast tumors in young patients with a second malignancy, the majority of these cancers were either grade 1 or grade 2 (10/13) while 3/13 were grade 3 carcinomas. Additionally, 10/13 of the cases were positive for estrogen receptor and negative for HER2, 2 cases were triple negative, and hormone receptor status was unknown in one case. 10/13 carcinomas were treated with mastectomy and the remaining 3 by lumpectomy. Lymph nodes were examined in 9 cases and one or more lymph nodes were found to be positive in 3 cases. Germline mutations panel (limited or complete) were available in 12 cases. Germline genetic alterations were found in three of the patients (3/12), as summarized in the Table 1. These included BRCA1 (2/12) and PTEN (1/12). Although variant of uncertain significance (VUS) mutations were also recognized in other genes e.g. ATM (1/12), SMAD4 (1/12) and MSH2 (1/12), those were not included in our analysis due to lack of current knowledge regarding their clinical significance.Additionally, 51 benign neoplasms were also diagnosed (e.g. benign nevi, thyroid adenomas, benign ovarian neoplasms, etc.). Nearly half (20/51) involved the female genital tract (uterus, cervix, or ovaries), 17 the skin and soft tissues, 4 the gastrointestinal tract, 8 the thyroid, and 1 the brain.Conclusions: Young women with BC are likely to have an underlying genetic predisposition for the development of BC and other malignancies. Although BRCA1 was the most common mutation observed, germline mutations of other genes were also seen. Therefore, genetic counselling, testing, and increased surveillance are extremely useful tools in managing the development of other associated malignancies in young women with BC.

Table 1: Summary of clinico-pathologic characteristics of BC with second malignanciesNo.Type of carcinomaGradePrognostic markersAssociated in-situ carcinomaAge at diagnosisSecondary diagnosisTimeline of second diagnosisInitial management of BCLymph node statusGenetic testing results1.Invasive lobular carcinoma1UnknownLobular carcinoma in situ39Malignant phyllodes tumorConcurrentMastectomyNegativeUnknown2.Invasive ductal carcinoma3Triple negativeDuctal carcinoma in situ36Squamous cell carcinoma, esophagus7 years laterMastectomyNegativeBRCA1+3.Invasive ductal carcinoma3Triple negativeNone38High grade serous carcinoma, ovary5 years laterMastectomyOne lymph node positiveBRCA1+4.Invasive ductal carcinoma with mucinous features1Estrogen receptor+/Progesterone receptor+/HER2-Ductal carcinoma in situ33Gastrointestinal stromal tumor, jejunum7 years laterMastectomyNegativeNegative5.Invasive ductal carcinoma2Estrogen receptor+/Progesterone receptor+/HER2-Lobular carcinoma in situ31Malignant phyllodes tumor7 years earlierMastectomyNegativeNegative6.Invasive ductal carcinoma2Estrogen receptor+/Progesterone receptor-/HER2-Ductal carcinoma in situ37Complex endometrial hyperplasia with atypia and leiomyoma with Fumarate hydratase features6 years laterMastectomyNot performedNegative7.Invasive ductal carcinoma2Estrogen receptor+/Progesterone receptor+/HER2-None36Hodgkin disease20 years earlierMastectomyNegativeNegative8.Invasive ductal carcinoma3Estrogen receptor+/Progesterone receptor+/HER2-Ductal carcinoma in situ29High grade squamous intraepithelial lesion1 year earlierMastectomyOne lymph node positiveNegative9.Invasive ductal carcinoma2Estrogen receptor+/Progesterone receptor+/HER2-Ductal carcinoma in situ36High grade squamous intraepithelial lesion1.5 year laterMastectomyOne lymph node positiveNegative10.Invasive ductal carcinoma2Estrogen receptor+/Progesterone receptor+/HER2-Ductal carcinoma in situ36High grade squamous intraepithelial lesion1 month earlierLumpectomyNegativeNegative11.Invasive ductal carcinoma1Estrogen receptor+/Progesterone receptor+/HER2-Ductal carcinoma in situ38Endometrioid adenocarcinoma10 months laterLumpectomyNot performedCowden syndrome (PTEN gene)12.Invasive mucinous carcinoma1Estrogen receptor+/Progesterone receptor+/HER2-Ductal carcinoma in situ41Papillary thyroid carcinoma14 years earlierLumpectomyNot performedNegative13.Invasive tubular carcinoma1Estrogen receptor+/Progesterone receptor+/HER2-Ductal carcinoma in situ37Malignant phyllodes tumorConcurrentMastectomyNegativeNegative

Citation Format: Indu Agarwal, Brian Finkelman, Luis Z. Blanco, Amir Behdad, Kalliopi Siziopikou. Associations and spectrum of genetic mutations in younger patients with breast carcinoma and additional malignancies [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS7-74.