c-erbB-2/c-erbA co-amplification indicative of lymph node metastasis, and c-myc amplification of high tumour grade, in human breast carcinoma

Abstract

Summary A panel of 73 samples, including 52 primary breast carcinomas, 10 normal breast tissues and 11 axillary lymph nodes, has been analysed for the presence of amplifications and gross structural alterations, in the oncogenes c-erbB-2, c-erbA, c-myc, N-myc, c-mos and c-Ha-ras. The tumours were also classified, graded and staged histopathologically and their DNA ploidy (42 samples) was determined by flow cytometry. Three breast cancer cell lines (MCF7, ZR-75-1 and T47D) were also included in the study. Amplification of c-erbB-2 was detected in 28% of the tumours, of which 91% had an increased steady-state level of c-erbB-2 mRNA. Amplification of c-erbA was found in 23% of tumours and was always associated with the amplification of c-erbB-2. Ten out of 12 (83%) tumours which had c-erbB-2 and c-erbA co-amplification had metastasised to axillary lymph nodes (P<0.006). However, the human thymidine kinase gene, which is present at the same chromosomal location as these two oncogenes (17q21-22), was amplified in only two tumours. Amplification of c-myc was detected in 21% of the tumours studied, of which 82% (P<0.005) were of histopathological grade 3 and none were of grade 1. Flow cytometry showed that 90% (P<0.01) of the analysed tumours with c-erbB-2 and c-erbA co-amplification, and 70% (P<0.1) of those with c-myc amplification were DNA aneuploid. This study demonstrates the potential value of c-myc amplification in the assessment of the tumour grade, rather than metastatic potential; and of the co-amplification of c-erbB-2 and c-erbA as a strong indicator of metastatic potential, rather than tumour grade.

C-myc amplification in breast cancer: a meta-analysis of its occurrence and prognostic relevance

“…The analysis included 29 reports (representing 26 distinct studies) that met the inclusion criteria. Twenty-six of the 29 reports were included in the estimation of the overall proportion of c-myc-amplified tumors (Escot et al, 1986;Cline et al, 1987;Varley et al, 1987;Bonilla et al, 1988;Guerin et al, 1988;Adnane et al, 1989;Garcia et al, 1989;Tavassoli et al, 1989;Tsuda et al, 1989;Zhou et al, 1989;Brouillet et al, 1990;Meyers et al, 1990;Munzel et al, 1991;Berns et al, 1992b;Borg et al, 1992;Roux-Dosseto et al, 1992;Kreipe et al, 1993;Nagayama and Watatani, 1993;Ottestad et al, 1993;Scorilas et al, 1993;Watson et al, 1996;Yamashita et al, 1993;Bieche et al, 1994;Harada et al, 1994;Contegiacomo et al, 1995;Lonn et al, 1995). Amplification data in Champeme et al (1994), Scorilas et al (1995) and Berns et al (1992) were excluded from estimation of the overall proportion, since they were originally reported in Bieche et al (1994), Scorilas et al (1993) and Berns et al (1992b), respectively.…”

“…Seven prognostic factors were analysed for their association with c-myc amplification: lymph node involvement (Escot et al, 1986;Cline et al, 1987;Varley et al, 1987;Adnane et al, 1989;Tavassoli et al, 1989;Berns et al, 1992a;Borg et al, 1992;Kreipe et al, 1993;Nagayama and Watatani, 1993;Scorilas et al, 1993;Champeme et al, 1994;Harada et al, 1994;Lonn et al, 1995), oestrogen receptor status (Escot et al, 1986;Varley et al, 1987;Adnane et al, 1989;Garcia et al, 1989;Berns et al, 1992b;Borg et al, 1992;Kreipe et al, 1993;Yamashita et al, 1993), progesterone receptor status (Escot et al, 1986;Adnane et al, 1989;Garcia et al, 1989;Berns et al, 1992b;Borg et al, 1992;Kreipe et al, 1993;Champeme et al, 1994), age (Escot et al, 1986;Guerin et al, 1988;Adnane et al, 1989;Berns et al, 1992a;Borg et al, 1992;Kreipe et al, 1993), menopausal status (Varley et al, 1987;Berns et al, 1992a;Borg et al, 1992;Yamashita et al, 1993), tumour size (Guerin et al, 1988;Adnane et al, 1989;…”

“…Exclusion of the two studies (Yamashita et al, 1993;Lonn et al, 1995), where HRs were estimated from the P-values, still resulted in approximately two-fold increases in risk. As with the individual prognostic factors, there was relatively little variation in Lonn, 1995Watson, 1993 PCR methods Borg, 1992Zhou, 1989Tsuda, 1989 slot blots Contegiacomo, 1995Harada, 1994Yamashita, 1993Scorilas, 1993Ottestad, 1993Nagayama, 1993Kreipe, 1993 Roux-Dossetto, 1992 Berns, 1992Munzel, 1991Meyers, 1990Brouillet, 1990Tavassoli, 1989Garcia, 1989Adnane, 1989Guerin, 1988Bonilla, 1998Varley, 1987Cline, 1987Escot, 1986 Southern blot the threshold used to define c-myc amplification, so its influence on associations with survival could not be assessed.…”

c-erbB-2 positive breast tumours behave more aggressively in the first years after diagnosis

“…These results were refuted by others (Ali et al, 1988;Zhou et al, 1989). Gene amplification of c-erbB-2 correlated with lymphnode involvement (Slamon et al, 1987;Zhou et al, 1987;Slamon et al, 1989;Guerin et al, 1989;Tavassoli et al, 1989), histological grade (Berger et al, 1988;Tavassoli et al, 1989;Tsuda et al, 1989, Paik et al, 1990, negative ERcontent Guerin et al, 1989;Zeillinger et al, 1989;Heintz et al, 1990), early recurrence (Zhou et al, 1987;Cline et al, 1987;Varley et al, 1987), short overall survival time Slamon et al, 1987;Varley et al, 1987;Slamon et al, 1989;Paik et al, 1990) and increased mitotic activity (Heintz et al, 1990;Ramachandra et al, 1990). All of these factors are considered to be bad prognostic indicators.…”

Amplification of c-erbB-2, int-2 and c-myc Genes in Node-Negative Breast Carcinomas: Relationship to Prognosis

“…These frequencies have, however, not been confirmed by other investigators (17,29,30). Although some studies have demonstrated a higher rate of c-myc amplification in node-positive than in node-negative primary tumours, a clear relationship between c-myc amplification and aggressive disease behaviour has not been demonstrated (25,31,32).…”