I read elsewhere MYC makes her-2 bad:
C-myc, not HER-2/neu, can predict recurrence and mortality of patients with node-negative breast cancer.
Schlotter CM, Vogt U, Bosse U, Mersch B, Wassmann K.
Frauenklinik Klinikum Ibbenbueren, Ibbenbueren, Germany.
C.Schlotter@Klinikum-Ibbenbueren.de
BACKGROUND: At present, node-negative, high-risk breast cancer patients cannot be identified with sufficient accuracy. Consequently, further strong prognostic factors are needed. METHODS: Among 181 node-negative breast cancer (NNBC) patients, c-myc and HER-2/neu oncogenes were identified prospectively using double differential PCR. The possible impact of amplification of those oncogenes on disease-free survival (DFS) and overall survival was examined. Furthermore, the possible effects of adjuvant therapies on rate of recurrence and mortality in oncogene-amplified NNBC patients were investigated. RESULTS: The prevalence rates for amplification of c-myc and HER-2/neu were 21.5% and 30.4%, respectively. On univariate analysis, c-myc-amplified NNBCs were associated with significantly shorter DFS at 36 months after the initial diagnosis (85.3% versus 97.3%). As compared with nonamplified cancers, HER-2/neu-amplified NNBCs did not exhibit any significant differences after 36 months and 95 months. Multivariate analysis indicated that c-myc amplification and tumour size, in contrast to HER-2/neu amplification, oestrogen receptor status, grading and age, were the only independent parameters for DFS. During the period of observation, we found no evidence for an impact of amplification of the oncogenes on overall survival in all cases. With respect to various adjuvant systemic therapies such as chemotherapy (cyclophosphamide, methotrexate, 5-fluorouracil; fluorouracil, epirubicin, cyclophosphamide) and endocrine therapy (tamoxifen), no significant differences were identified in oncogene-amplified NNBC patients in terms of DFS and overall survival. However, those c-myc-amplified NNBC patients who did not receive adjuvant systemic therapy exhibited significantly shorter DFS and overall survival as compared with c-myc-nonamplified patients. CONCLUSION: C-myc amplification appears to be a strong prognostic marker with which to predict early recurrence in NNBC patients. C-myc-amplified NNBC patients without adjuvant systemic therapy experienced shorter DFS and overall survival.
Numerous clinical studies have proved axillary lymph node status to be the dominant factor for prognosis and prediction of DFS and OS in breast cancer patients. The fact of the matter is that even among NNBC patients 25–30% can be expected to progress or even die. The advantage conferred by adjuvant chemotherapy or endocrine therapy was examined in randomized studies [2,3,8,9,35-38]. Because adjuvant therapies may positively impact on outcome in only around 15%, the costs of these therapies make their routine application in all NNBC patients inappropriate [1]. For this reason, predictive factors that accurately define subgroups of NNBC patients who may benefit from adjuvant systemic therapy would be a great advantage.
In the present study the oncogenes c-myc and HER-2/neu were examined with regard to their ability to predict DFS, OS and rate of recurrence, as well as mortality. All patients were randomly selected from one department (Frauenklinik Klinikum Ibbenbueren, Ibbenbueren, Germany). C-myc amplification was identified in 21.5% and HER-2/neu amplification in 30.4%. Berns and coworkers [12-14] reported amplification of c-myc in 20% and of HER-2/neu in 24% using a standard southern blot technique. In a selected high-risk cohort of NNBC patients, Roux-Dosseto et al. [26] applied the same method and found prevalence rates for c-myc and HER-2/neu amplification of 25% and 31%, respectively. Those oncogenes were assessed in the present study using a double differential PCR technique [17,18,40,43]. Using this method, Brandt et al. [17] found c-myc to be amplified in 19.7% and HER-2/neu in 16.7% of breast cancers, without consideration of nodal status; coamplification of those oncogenes was present in 7%. In the present study, simultaneous amplification of both oncogenes was observed in 12.2%. As in the present investigation, Roux-Dosseto et al. [26] found that c-myc amplification among NNBC patients was significantly associated with earlier recurrence in univariate and multivariate analyses. However, HER-2/neu-amplified NNBC patients did not have the same outcome. Accordingly, c-myc amplification appears to be an independent prognostic marker, which has greater predictive power than does oestrogen receptor status and tumour grade. As early as 1992, Berns and coworkers [11,12,14] reported that patients with c-myc-amplified breast cancers had an unfavourable prognosis.
The first study to mention possible prognostic importance of HER-2/neu gene amplification was reported in 1987 by Slamon et al. [27]. That study included 187 patients with NNBC and node-positive breast cancer; by univariate and multivariate analyses, it revealed that HER-2/neu amplification correlated very closely with shorter DFS and OS in a subgroup of 87 node-positive patients. In 1993, in an analysis of 210 patients, Press et al. [7] found that amplification of HER-2/neu correlated with unfavourable prognosis with respect to DFS.
Attempts by other investigators to confirm these findings were met with various degrees of success. Some studies claimed that HER-2/neu status was an independent predictive factor in the case of breast cancer, whereas other studies could not confirm this [6,14,16,19,29,30]. It is certainly of great interest to the clinician that only two out of five studies including more than 100 patients and with a follow-up period of at least 3 years attributed some prognostic value to HER-2/neu amplification among patients with NNBC [6,7,16,19,28]. Almost all of the studies that dealt with HER-2/neu status and DFS, as well as OS, showed no benefit of this oncogene in the prognosis of NNBC patients. In a survey conducted by Ravdin and Chamness [24], only one [22] of 11 studies concerning immunohistochemical overexpression of HER-2/neu indicated a significant result with respect to OS in multivariate analysis.
In the present study, 19 out of 39 c-myc-amplified patients received chemotherapy, 15 patients received endocrine therapy and five patients received no further therapy. The greatest recurrence rates were noted in the group of patients who received no therapy (20%) and in those who received chemotherapy (16%). The lowest recurrence rate of 7% was seen in patients treated with tamoxifen. All patients who received endocrine therapy (n = 99) were characterized by positive oestrogen and/or progesterone receptor status. The proto-oncogene c-myc can be upregulated by oestrogen stimulation of hormone-dependent breast cancer cells. Endocrine therapy with the antioestrogen tamoxifen can mediate the downregulation of c-myc, culminating in cell cycle arrest [44]. Berns et al. [12] reported that 38% of patients with amplification of c-myc or with coamplification of c-myc and HER-2/neu profited from endocrine therapy. C-myc-amplified patients affected by metastatic disease showed a tendency toward longer DFS with endocrine therapy, as compared with shorter DFS following second-line chemotherapy. However, the minor rate of response after chemotherapy did not correlate with OS. The poorer responses to chemotherapy among patients with c-myc-amplified tumours in the present study (recurrence rate 16%) may be in agreement with experimental findings in erythroleukaemia cells that the degree of cis-platinum resistance correlated directly with the level of c-myc expression [45].
In the present study, 26 out of 55 HER-2/neu-amplified patients received chemotherapy, 22 patients received endocrine therapy and seven patients received no further therapy. In total, low recurrence rates of 3.8%, 4.5% and 0% were found in the above-mentioned therapy groups, respectively (Table 3). Compared with nonamplified patients administered the same therapies, no significant differences with regard to DFS and OS were observed. In contrast to that finding, c-myc-amplified patients not administered adjuvant systemic therapy exhibited a significantly shorter DFS and OS than did nonamplified patients who also received no adjuvant systemic therapy. However, the therapy groups analyzed in the present study are small, and therefore we recommend careful interpretation of the findings.
Higher recurrence rates or poor response to endocrine treatment with tamoxifen in patients with HER-2/neu-amplified hormone receptor positive tumours, as reported in studies in node-positive or metastatic breast cancer [12,15,32], were not observed in the present study. Although deregulated HER-2/neu activity can strongly stimulate cytoplasmic signalling pathways, which in turn impinge on c-myc at multiple levels causing its deregulated expression [46], this scenario does not appear to be active in NNBC because the recurrence rate of 22 c-myc and HER-2/neu coamplified patients was only 9%. However, among those patients in whom coamplification of c-myc and HER-2/neu was absent the recurrence rate was lower (4/109 [3.6%]). Differences in the numbers of recurrences and deaths can be accounted for by the fact that some deaths were not related to tumours.
CONCLUSION
C-myc amplification appears to represent a prognostic marker with which early recurrence may be predicted in NNBC patients. C-myc-amplified NNBC patients who were not administered adjuvant systemic therapy suffer shorter DFS and OS. C-myc could be used together with the tumour-associated protease urokinase-plasminogen activator and its inhibitor (i.e. plasminogen activator inhibitor-1), after further randomized studies have been conducted, to confirm whether NNBC patients should receive adjuvant systemic therapy [47-49].
So...what bout a brief interruption?
Brief Inactivation of MYC Oncogene Permanently Reverses Tumor Cell Production Background: Cancer therapies designed to inactivate oncogenes (mutated normal genes that permit unregulated cell growth) might be expected to have serious toxicities because they also target critical pathways in normal cells. However, results from a recent study suggest that the brief inactivation of oncogenes during cancer treatment may lead to the sustained regression of tumors without inducing significant toxicity. Advance: The investigators used a special genetic construct, the tetracycline regulatory system, with the MYC oncogene to conditionally turn on or off (activate or inactivate) the expression of the gene in a transgenic mouse model of MYC-induced malignant bone tumor, in which the genome was altered by the transfer of genes. The studies demonstrated that in the tumor-bearing mice, brief inactivation of MYC resulted in much slower tumor cell growth and the development of the bone cancer cells into mature bone. Surprisingly, subsequent re-expression of MYC not only failed to induce regrowth of the tumors, but actually produced cell death. Similar results were observed in laboratory tests using bone cancer cells. Implications: The authors conclude that brief MYC inactivation permanently reverses the tumor-related characteristics of MYC-induced tumors, perhaps by causing changes in the tumor cells that disrupt the ability of MYC to sustain tumor cell production. Moreover, the tumor-related characteristics do not necessarily reappear upon reactivation of the oncogene. These results suggest that drugs that inactivate oncogenes intermittently and briefly may be effective, nontoxic cancer therapeutics. Jain M, Arvanitiz C, Chu K, Daway W, Leonhardt E, Trinh M, Sundberg CD, Bishop JM, Felsher DW: Sustained loss of a neoplastic phenotype by brief inactivation of MYC. Science 297: 102-104, 2002.
Linear Mode
