FGFR-1 amplification in metastatic lymph-nodal and haematogenous lobular breast carcinoma

Abstract

BackgroundLobular breast carcinoma usually shows poor responsiveness to chemotherapies and often lacks targeted therapies. Since FGFR1 expression has been shown to play pivotal roles in primary breast cancer tumorigenesis, we sought to analyze the status of FGFR1 gene in a metastatic setting of lobular breast carcinoma, since promising FGFR1 inhibitors has been recently developed.MethodsFifteen tissue metastases from lobular breast carcinomas with matched primary infiltrative lobular breast carcinoma were recruited. Eleven cases showed loco-regional lymph-nodal and four haematogenous metastases.FGFR-1 gene (8p12) amplification was evaluated by chromogenic in situ hybridization (CISH) analysis. Her-2/neu and topoisomerase-IIα gene status was assessed. E-cadherin and Hercept Test were also performed. We distinguished amplification (>6 or cluster of signals) versus gains (3–6 signals) of the locus specific FGFR-1 gene.ResultsThree (20%) primary lobular breast carcinomas showed >6 or cluster of FGFR1 signals (amplification), six cases (40%) had a mean of three (range 3–6) chromogenic signals (gains) whereas in 6 (40%) was not observed any abnormality. Three of 15 metastasis (20%) were amplified, 2/15 (13,4%) did not. The ten remaining cases (66,6%) showed three chromogenic signals.The three cases with FGFR-1 amplification matched with those primary breast carcinomas showing FGFR-1 amplification. The six cases showing FGFR-1 gains in the primary tumour again showed FGFR-1 gains in the metastases. Four cases showed gains of FGFR-1 gene signals in the metastases and not in the primary tumours. Her-2/neu gene amplification was not observed in all cases but one (6%) case. Topoisomerase-IIα was not amplified in all cases.Conclusions1) a subset of metastatic lobular breast carcinoma harbors FGFR-1 gene amplification or gains of chromogenic signals; 2) a minor heterogeneity has been observed after matching primary and metastatic carcinomas; 3) in the era of tailored therapies, patients affected by the lobular subtype of breast carcinoma with FGFR1 amplification could be approached to the new target biological therapy such as emerging FGFR-1 inhibitors.

Targeting FGFR Signaling in Cancer

“…38, 41, 42; Table 1). In breast cancer, amplification of FGFR1-and/or 11q12-14 (which contains CCND1, FGF3, FGF4, and FGF19) have been observed in 23% of hormone receptor-positive (HR þ ), 27% of HER2-amplified, and 7% of triple-negative cases and is predictive for early relapses and poor outcome (43)(44)(45)(46)(47). Many FGFR1-amplified breast cancer cell lines are addicted to FGFR1 amplification (45,48,49), and FGFR1 amplification also drives resistance to endocrine therapy (48).…”

“…In breast cancer, amplification of FGFR1-and/or 11q12-14 (which contains CCND1, FGF3, FGF4, and FGF19) have been observed in 23% of hormone receptor-positive (HR þ ), 27% of HER2-amplified, and 7% of triple-negative cases and is predictive for early relapses and poor outcome (43)(44)(45)(46)(47). Many FGFR1-amplified breast cancer cell lines are addicted to FGFR1 amplification (45,48,49), and FGFR1 amplification also drives resistance to endocrine therapy (48). FGFR2 amplification (4% of triple-negative breast cancer, 4%-9% of gastric cancers) is associated with the maintenance of tumor-initiating cells (50), poorer prognosis (51,52), and high sensitivity to FGFR inhibitors (49,50,53).…”

Current Status of Fibroblast Growth Factor Receptors Targeted Therapies in Breast Cancer

“…Always in the context of BC, amplification of FGFR1-and/or 11q12-14, which is a chromosomal region containing CCND1, FGF3, FGF4, and FGF19, have been detected in 23% of hormone receptor-positive (HR+) BC, 27% HER2-positive BC, and 7% TNBC and it has been shown to be a prognostic indicator for early relapses and poor patients' outcome [32][33][34][35][36]. As shown by in vitro studies, the Accordingly to several studies, FGFR2 amplifications -shown to occur in 4% of TNBC-as well as activating mutations of the receptor, have been associated with high sensitivity to FGFR inhibitors [37][38][39] and maintenance of tumour-initiating cells [38].…”

“…As shown by in vitro studies, the Accordingly to several studies, FGFR2 amplifications -shown to occur in 4% of TNBC-as well as activating mutations of the receptor, have been associated with high sensitivity to FGFR inhibitors [37][38][39] and maintenance of tumour-initiating cells [38]. [24, [32][33][34][35][36][37], which has shown transforming potential in several in vivo models, conferring also sensitivity to FGFR inhibitors [35] and ability to drive resistance to endocrine therapy [24] as previously described; FGFR2 translocation, which in preclinical models exhibited transforming potential and sensitivity to FGFR inhibitors [40]; FGFR2 amplifications (4%, [38]), which in preclinical models conferred resistance to FGFR inhibitors [37][38][39]. In different solid tumors, including breast cancer, various studies in literature have described FGFRs activating mutations: FGFR1: two point mutations (K656E and N546) have observed in vitro affecting the intracellular domain of the receptor and therefore acting as activating mutations [41,42].…”

Fibroblast growth factor receptors in malignant tumors

“…Это происходит за счет активации матриксной металлопротеина-зы-3 и деградации Е-кадхерина [36]. Последнее является характерной особенностью дольково-го рака молочной железы, а FGFR1 при данном подтипе рака рассматривается как терапев-тическая мишень [37]. Также интересно, что амплификация FGFR1 характерна в большей степени для инвазивного рака, в отличие от карциномы in situ.…”