Epidermal growth factor receptor and other oncogenes as prognostic markers.

Analysis of epidermal growth factor receptor (EGFr) and estrogen receptor (ER) was performed on tumor samples from 231 patients with operable breast cancer followed for up to 6 years after surgery. The median duration of follow-up in patients still alive at the time of analysis was 45 months. Thirty-five percent of patients (82) had tumors greater than 10 fmol/mg of 125I-EGF binding (EGFr+) and 47% (109) had cystolic ER concentration greater than 5 fmol/mg (ER+), with a marked inverse relationship between EGFr and ER (P less than .00001). EGFr was second only to axillary-node status as a prognostic marker for all patients in terms of both relapse-free and overall survival in univariate analysis (P less than .001, log-rank EGFr + v EGFr-). For patients with histologically negative axillary nodes, EGFr was superior to ER in predicting relapse and survival (P less than .01 and P less than .005, respectively, compared to P less than .1 and P less than .1, log-rank). In a multivariate (Cox model) analysis, only EGFr--out of EGFr, ER, size, and grade--was predictive for either relapse-free or overall survival for patients with node-negative disease (P = .052 and P = .026, respectively). One hundred eighty-seven case patients in the series were assessed for neu expression immunochemically, and 31 were positive. There was a highly significant increased risk of relapse and death in the positive group. In patients with otherwise good prognostic markers (ER+, node-negative, well-differentiated tumors), neu expression predicted for significantly worsened overall survival.(ABSTRACT TRUNCATED AT 250 WORDS)     

Epidermal growth factor receptor (EGFr) status associated with failure of primary endocrine therapy in elderly postmenopausal patients with breast cancer

We have used primary endocrine therapy for 61 elderly women with operable breast cancer (median age 77 years). Eleven patients (18%) had complete and 24 (39%) partial tumour regression, 12 (20%) had stable disease for a minimum of six months and 14 (23%) no response. Salvage surgery was undertaken in the 14 with no response and 8/9 with progressive disease following initial response, thus samples were available from relapse patients only. Assays for EGFr (two point radioreceptor assay) and oestrogen receptors (ER) (dextran coated charcoal method and an immunohistochemical method) were performed on 20/22 patients. Ten of these 20 tumours were EGFr+ (greater than 10 fmol mg-1 binding) and 9/13 patients progressing within six months had EGFr+ tumours. 15/22 were available for ER evaluation and there was no such association with ER status. EGFr status was also associated with early recurrence after surgery and death in the endocrine failure group (P less than 0.005 and P less than 0.05 respectively). Of a control population of 33 patients (median age 72 years) treated by primary surgery, only 6 were EGFr+. In this group early relapse was predicted by EGFr status, but not by ER status (median disease free survival for EGFr+ patients 15 months, and for EGFr- patients 40 months, P less than 0.01, logrank test). There was a significantly higher proportion of EGFr+ tumours in the endocrine failure group compared with the control population (P less than 0.001). EGFr status is a marker for rapid early progression on primary endocrine therapy and the development of non-excisional methods of EGFr analysis would allow better directed therapeutic decisions.     

A prognostic score in histological node negative breast cancer

Between October 1977 and December 1983, 379 consecutive patients have been treated for unilateral, non-metastatic breast cancer, either with conservative (n = 205) or radical surgery (n = 174), with axillary dissection in all the cases. None of them had histologically proved lymph node involvement. Oestrogen receptor (ER) and progesterone receptor (PR) levels were measured on each tumour. Levels greater than 5 fmol mg-1 cytosolic protein were considered as positive for both ER and PR. At 5 years, overall survival (OS) and disease-free survival (DFS) are respectively 88% and 78%. Unifactorial analysis using Kaplan and Meier estimates and the log rank test revealed that OS was significantly related to age (P less than 0.05), tumour size (P less than 0.001), histological grading (SBR) (P less than 0.01), ER (P less than 0.001) and PR (P less than 0.001). DFS was significantly related to the same factors. Menopausal status, number of breast tumour foci and previous familial history of breast cancer were not significant. Multifactorial analysis revealed that DFS was significantly related to age (bad prognosis (b.p.) less than or equal to 37 years old), tumour size and histological grading (b.p. SBR = 3), and that OS was significantly related to tumour size and PR (b.p. PR less than or equal to 5 fmol mg-1 protein). A prognostic score has been constructed for both DFS and OS. These scores divide our patients into three significantly different (P less than 0.0001) groups with good, intermediate and bad prognosis.     

In vitro clonogenic growth and metastatic potential of human operable breast cancer

In 254 patients with operable [International Union against Cancer (1972) Stages I, II, and III] breast cancer, the relations between in vitro clonogenic growth in soft agar of primary breast cancer tumors and their metastatic potential expressed by the relapse-free survivals (RFS) as well as overall survivals were studied. Sixty-four % (163 of 254) of cancers formed distinct colonies (30 or more colonies in a single dish, or 10 or more colonies in plural dishes). Other breast cancers (36%, 91 of 254) were designated to be negative for the clonogenicity. There was no correlation between the positive or negative clonogenicity and clinicopathological characteristics in breast cancer patients, including the age of patients, menopausal status, tumor size, T classification, International Union against Cancer stage, histological type (Japanese Breast Cancer Society), histologically proved axillary lymph node metastasis, and estrogen receptor (ER). At the time of median follow-up of 43 mo (range, 25 to 61 mo) after mastectomy, a recurrence of malignancy occurred in 19.0% (31 of 163) of the patients with positive clonogenic tumors, and in 8.8% (8 of 91) of those with negative clonogenic tumors (P = 0.03). There also was a significant difference (P less than 0.03 by log rank test, P less than 0.05 by generalized Wilcoxon test) in RFS curves between positive and negative clonogenicity groups. These differences in RFS were also noted in Stage II patients in favor of the negative colony formation group. In ER-negative cancer patients, the RFS of patients with positive clonogenic cancers was shown to be worse (P less than 0.03 by log rank test, P less than 0.05 by generalized Wilcoxon test) than patients with negative clonogenic cancers. There was no difference in RFS in ER-positive cancer patients. There was a trend (P = 0.09 by log rank test) of worse overall survival rate in patients with positive clonogenic growth. In a multivariate comparison using the principal component analysis composed of factors including positive node, T classification, histological type, age, ER, and colony formation, the clonogenicity showed a significant effect on the recurrence of malignancy and also on the survival of the patients after mastectomy. In conclusion, in vitro clonogenic growth of the primary tumor of breast cancer was shown to be one of the independent factors of metastatic potential in operable breast cancer patients after mastectomy.     

Mutant p53, EGF receptor and c-erbB-2 expression in human breast cancer.

p53 expression was studied in 111 primary breast cancers with a monoclonal antibody (PAb240) that reacts with an epitope in mutant p53. Epidermal growth factor receptors (EGFr) and oestrogen receptors (ER) measured by ligand binding, c-erbB-2 expression assessed by immunochemistry and lymph node status were compared with p53 staining. Fifty-nine tumours (53%) were positive for p53, and this correlated with EGFr expression (P less than 0.02), which is a known poor prognostic factor. Eighteen out of 59 p53+ tumours expressed c-erbB-2 versus 4 out of 52 p53- tumours assessed on paraffin sections. However, assessing c-erbB-2 by Southern blotting and immunochemistry on frozen sections showed that 20 out of 59 p53+ tumours overexpressed or had amplified c-erbB-2 compared with 15 out of 52 p53- tumours (not significant). Mean EGFr concentration in p53+ tumours was 31 fmol per mg of membrane protein versus 14 fmol mg-1 in p53- tumours. Cytoplasmic staining was the most frequent pattern found for p53, but some cases showed cytoplasmic plus nuclear staining, or focal cells with predominantly nuclear staining. Thus, abnormal p53 is the commonest oncogene abnormality described in breast cancer. The association with EGFr expression suggests that these oncogenes interact in the pathogenesis of breast cancer.     

Low number of examined lymph nodes in node-negative breast cancer patients is an adverse prognostic factor.

BACKGROUND: The aim of the study was to determine whether the number of lymph nodes removed at axillary dissection is associated with recurrence and survival in node-negative breast cancer (NNBC) patients. PATIENTS AND METHODS: We retrospectively reviewed the medical records of 1606 women with pathologically node-negative T1-T3 invasive breast cancer. Median follow-up was 61 months (range 2-251). Potential prognostic factors assessed included: number of axillary lymph nodes examined, age, menopausal status, tumor size, histological type, tumor grade, estrogen receptor(ER), progesterone receptor (PR) and HER2. RESULTS: At 5 years, relapse-free survival (RFS) rate was 85% and breast cancer-specific survival (BCSS) rate was 94%. In univariate analysis, factors significantly associated with lower RFS and BCSS were: fewer than six lymph nodes examined (RFS, P = 0.01; BCSS, P = 0.007), tumor size >2 cm, grade III, negative ER or PR. Statistically significant factors for lower RFS and BCSS in multivariate analysis were: fewer than six lymph nodes examined [RFS, hazard ratio (HR) 1.36, P = 0.029; BCSS, HR 1.87, P = 0.005], tumor size >2 cm, tumor grade III and negative PR. CONCLUSIONS: Examination of fewer than six lymph nodes is an adverse prognostic factor in NNBC because it could lead to understaging. Six or more nodes need to be examined at axillary dissection to be confident of a node-negative status. This may be useful, in conjunction with other prognostic factors, in the assessment of NNBC patients for adjuvant systemic therapy.     

Tumor angiogenesis: a new significant and independent prognostic indicator in early-stage breast carcinoma.

BACKGROUND: Axillary lymph node status has been the most important prognostic factor in operable breast carcinoma, but it does not fully account for the varied disease outcome. More accurate prognostic indicators would help in selection of patients at high risk for disease recurrence and death who are candidates for systemic adjuvant therapy. Our recent findings indicated that microvessel density (count or grade) in invasive breast carcinoma (a measure of tumor angiogenesis) is associated with metastasis and thus may be a prognostic indicator. PURPOSE: This study was designed to further define the relationship of microvessel density with overall and relapse-free survival and with other reported prognostic indicators in breast carcinoma. METHODS: In a prospective, blinded study of 165 consecutive patients, the microvessels within primary invasive breast carcinoma were highlighted by immunocytochemical staining to detect factor VIII-related antigen. Using light microscopy, we counted microvessels per 200x field in the most active areas of neovascularization and graded microvessel density. These findings were correlated, by univariate and multivariate analyses, with overall and relapse-free survival, axillary node status, and other prognostic indicators (median follow-up, 51 months). RESULTS: There was a highly significant (P < or = .001) association of microvessel density with overall survival and relapse-free survival in all patients, including node-negative and node-positive subsets. All patients with breast carcinomas having more than 100 microvessels per 200x field experienced tumor recurrence within 33 months of diagnosis, compared with less than 5% of the patients with breast carcinoma having 33 or fewer microvessels per 200x field. Moreover, microvessel density was the only statistically significant predictor of overall survival among node-negative women (P < .001). Only microvessel density (P < .001) and histologic grade (P = .04) showed statistically significant correlations with relapse-free survival in the node-negative subset. CONCLUSIONS: Microvessel density in the area of the most intense neovascularization in invasive breast carcinoma is an independent and highly significant prognostic indicator for overall and relapse-free survival in patients with early-stage breast carcinoma (I or II by International Union Against Cancer criteria). IMPLICATIONS: Such an indicator would be useful in selection of those node-negative patients with breast carcinoma who are at high risk for having occult metastasis at presentation. These patients could then be given systemic adjuvant therapy.     

Response to endocrine manipulation and oestrogen receptor concentration in large operable primary breast cancer

Forty-three patients with large (greater than or equal to 4 cm) but operable carcinoma of the breast have been treated by endocrine manipulation before definitive local surgery. This has allowed the study of the relationship between response to therapy and pretreatment oestrogen receptor (ER) concentration, as measured by a dextran-coated charcoal adsorption method. Premenopausal patients (17) were treated by surgical (4) or medical (13) oophorectomy. Post-menopausal patients (26) received either tamoxifen (10) or an aromatase inhibitor (16). Response was assessed from statistical analysis of the changes in tumour size. On completion of 12 weeks of endocrine therapy, there was significant regression of tumour size in 18 of the 43 patients. All 18 patients had tumours with ER concentrations of greater than or equal to 20 fmol mg-1 cytosol protein. Conversely all patients except one progressing on treatment had tumours with ER concentrations of less than 20 fmol mg-1 cytosol protein. This relationship applied for both premenopausal and post-menopausal patients. The overall response rate of patients with tumours of ER concentration greater than or equal to 20 fmol mg-1 cytosol protein was 60%.     

Relationship of PS2 with response to tamoxifen therapy in patients with recurrent breast cancer.

PS2, an oestrogen-inducible protein, was measured in the cytosol of 230 primary tumours from patients who were subjected to first-line tamoxifen therapy for advanced disease without prior adjuvant therapy with tamoxifen. PS2 correlated positively with oestrogen receptor (ER, P < 0.01) and progesterone receptor content (PgR, P < 0.001), and with the length of progression-free survival (PFS, P = 0.05). Although not statistically significant, higher levels of PS2 (> or = 10 ng mg-1 protein) were also associated with increased probability of response to tamoxifen treatment and a longer total post-relapse survival (PRS). ER, PgR, menopausal status, site of disease and prior adjuvant chemotherapy were all associated with response to tamoxifen therapy and with PFS. In multivariate analysis for PFS, low levels of ER and PgR, visceral metastasis, a disease-free interval of less than 1 year and prior adjuvant chemotherapy were all significantly associated with an increased probability of a rapid disease progression after start of tamoxifen therapy. In the subset of 83 tumours with intermediate levels of ER and PgR (both > or = 10, but not both > or = 75 fmol mg-1 protein), PS2 was positively related with the length of PFS (P < 0.01) and PRS (P < 0.05). PS2 remained the strongest factor in multivariate analysis for PFS (P < 0.01) in this ER/PgR intermediate subgroup, but was not of predictive value in univariate or multivariate analysis for both PFS and PRS in tumours classified as ER/PgR low or high (> or = 75 fmol mg-1 protein). It is concluded that PS2 status may be used as a parameter, additional to ER and PgR, for better refinement of prediction of response to tamoxifen treatment in advanced breast cancer patients especially with intermediate ER/PgR levels in their primary tumour.     

Outcome of non-metastatic male breast cancer: 118 patients

Studies concerning adjuvant systemic therapy and prognosis in male breast carcinoma (MBC) are limited. We aimed to evaluate outcome of the changing practices of adjuvant systemic treatment and survival in operable MBC patients over the last two decades. The medical records of 148 MBC patients followed between the years 1986 and 2009 at 7 cancer center were evaluated retrospectively. One hundred and eighteen operable non-metastatic patients had sufficient data were included the study. One hundred and eighteen operable MBC were found to be eligible. Median age was 60 (range 29-83) years. Thirty-two percent of the patients had T3-4 tumors. Half of the patients had axillary lymph node-positive disease. The proportion of positivity of estrogen receptor(ER), progesterone receptor (PgR), and HER2 status were 82.9, 75.8, and 23.4%, respectively. Only, 7 patients had triple negative (TN). Adjuvant hormonotherapy was advised for 76.8% whereas adjuvant chemotherapy for 73.7% of the patients. Median follow-up was 40.9 months (range 3.8-186 months). Locoregional and/or distant recurrence developed in thirty-eight patients (32.2%). Twenty-three patients died during the follow-up period. Five-year disease-free survival (DFS) was found to be 60%, whereas overall survival (OS) was 82%. Larger tumor size and lymph node positivity were statistically significant poor prognostic factors for OS. Although statistical insignificant, patients with HER2-positive tumors have worse DFS (52 vs. 120 months, log rank P = .73) and OS (85 vs. 144 months, log rank P = .30) than HER2-negative ones. Although the frequency of the use of adjuvant systemic therapy in MBC has been increasing and survival rates improving for the last decades, lymph node status and tumor size are still the most important determining factors for prognosis. There is a need for further prognostic information in men with HER2-positive or TN breast cancer.     

Prognosis of node-positive breast cancer patients who underwent parasternal lymph node biopsy during surgery followed by doxorubicin- or mitoxantrone-containing adjuvant chemotherapy

The authors examined the survival rates of 60 patients with breast cancer who underwent parasternal lymph node biopsy during surgery with axillary lymph node dissection and had histologically confirmed axillary node metastasis followed by adjuvant doxorubicin- or mitoxantrone-containing combination chemotherapy to ascertain whether administration of anthracycline or its analogue improved the prognosis of both axillary and parasternal node-positive patients. The overall survival rate (OS) for the parasternal node-positive patients (n=13, 21.7%) was 30.6%, and relapse-free survival rate (RFS) fell to 0% at the 104-month follow-up. Although the survival rate for all axillary node-positive patients was similar to those in previous reports, the OS and RFS for both axillary and parasternal node-positive patients were significantly worse than that for axillary node-positive and parasternal node-negative patients, despite treatment with adjuvant doxorubicin- or mitoxantrone-containing combination chemotherapy. Other intensive adjuvant treatment strategies are needed to reduce distant metastases for high-risk breast cancer patients having both axillary and parasternal nodes positive.     

Biological markers as indicators of response to primary and adjuvant chemotherapy in breast cancer

Interest in translational studies on breast cancer is presently devoted to identify biological predictors of treatment response. In patients with operable breast cancer, subjected to primary and adjuvant chemotherapy, we analyzed the predictivity on objective clinical response and relapse-free survival of biological markers related to different cellular aspects and functions. Tumour proliferative rate (evaluated as the (3)H-thymidine-labelling index, TLI), oestrogen and progesterone receptors (ER and PgR, evaluated by the dextran-coated-charcoal method), nuclear DNA ploidy and the immunocytochemical expression of p53, bcl-2 and bax proteins were determined before primary treatment, at the time of diagnosis, and after primary chemotherapy, at surgery. Objective clinical response was significantly related only to pre-treatment p53 expression or PgR status, with a higher rate for tumours not expressing than for those expressing p53 (94% vs. 72%), as well as for PgR-negative (PgR(-)) than for PgR-positive (PgR(+)) tumours (86% vs. 68%). In the overall series, 8-year clinical outcome was significantly related only to post-treatment steroid receptors. In particular, higher 8-year relapse-free survival rate was observed for patients with ER(-) or PgR(-) than for those with ER(+) (64% vs. 38%) or PgR(+) (53% vs. 37%) tumours. Such findings held true even within the sub-set of patients who received adjuvant post-operative chemotherapy, i.e., those with node-positive (N(+)) or ER(-)/node-negative (N(-)) tumours, among whom also rapid proliferation or the presence of apoptosis-favouring markers (bcl-2(-) or bax(+), singly and in association) on surgical specimens identified a sub-set of women who benefited from systemic treatment. The different biological markers were variously indicative of clinical outcome, with a predictivity on tumour shrinkage for p53 and PgR, detected before primary chemotherapy, and on long-term follow-up for ER, PgR and, to a lesser extent, TLI and apoptosis-modulating markers. Int. J. Cancer (Pred. Oncol.) 84:580-586, 1999.     

Is aryl hydrocarbon hydroxylase activity a new prognostic indicator for breast cancer?

Aryl hydrocarbon hydroxylase (AHH) activity was measured in the breast tumours of 153 primary and 17 recurrent cancer patients, and in 18 patients with benign breast tumour. All operations were carried out in 1983-84. The cytosolic fraction was collected for steroid receptor determination, and microsomes were separated for AHH assay from the same tissue samples. The AHH distribution was wide and highly skewed in all groups. About 10% of the samples showed activities below detection limit. The medians and ranges for primary cancers were 34 (less than 5-2683), for recurrent cancers 40 (20-239) and for benign tumours 11 (less than 5-37) fmol min-1 mg-1 protein. After logarithmic transformation, the mean AHH activities of cancer samples differed significantly from those of benign tumours. The logarithm of AHH activity (log AHH) correlates positively with axillary lymph node status, and negatively with steroid receptor levels. The development of the disease and the survival of the patients were followed for 4 years. The survival and the disease-free interval of the cancer patients who had low AHH activity was significantly higher than that of the high AHH group. The multivariate analysis with Cox's proportional hazad model showed primary tumour size, progesterone receptor concentration, nodal status and log AHH to be the most important independent prognostic factors for survival, while the occurrence of metastases, log AHH and tumour size were the equivalent factors for the disease-free interval in primary breast cancers. We conclude that AHH activity may reflect the overall malignant potential of breast cancer tissue.     

Estrogen-receptor status and response to chemotherapy in early and advanced breast cancer

Summary The value of estrogen receptor (ER) status in the prediction of tumor response to combination chemotherapy was retrospectively analyzed in breast cancer patients selected for prospective controlled trials of chemotherapy (85 with advanced disease and 256 with operable tumors). All patients were previously untreated with either chemotherapy or endocrine therapy, and in all instances drug therapy was applied at the time of primary treatment. The ER status was considered positive in 54% of women with advanced disease and in 70% of women with operable breast tumor and positive axillary nodes, respectively. About 12% of patients were considered to have borderline ER. The response to drug therapy (complete plus partial remission in advanced breast cancer and 3-year relapse-free survival after mastectomy, respectively) was not significantly different between ER+ and ER—tumors. The comparative results of ER+ vs ER—patients were similar whether the cutoff point for ER+ tumors was >5 or >10 fmol/mg cytosol protein. The present results indicate that in advanced and early breast cancer combination chemotherapy is effective regardless of ER status. Therefore, in the presence of ER+ tumors there is no reason to delay the early administration of effective chemotherapy. This is particularly true both in the presence of rapidly progressing metastatic disease and in the adjuvant setting.Presented in part at the 15th Annual Meeting of the American Society of Clinical Oncology (New Orleans, May 14–15, 1979)     

Primary systemic therapy for operable breast cancer.

Eighty-eight patients presenting with operable breast cancer of 4 cm or greater in diameter (T2, T3, N0, N1, M0) have received primary systemic therapy. Response was assessed following 12 weeks of systemic therapy by linear regression analysis of changes in tumour volume. Definitive locoregional surgery (mastectomy n = 82, wide local excision n = 6) was performed on completion of systemic therapy (3-6 months). Response was observed in 24 (39%) of the 61 patients who received endocrine therapy; all 24 had tumours with an oestrogen receptor (ER) concentration of greater than or equal to 20 fmol mb-1 cytosol protein. Cytotoxic therapy was reserved for patients with tumours of ER concentration less than 20 fmol mg-1 cytosol protein (n = 27) or when endocrine therapy had failed (n = 20). Response was observed in 34 patients (72%). The overall survival rate at 3 years was 86%, with 81% remaining free from local relapse. We propose that the treatment policy outlined in this paper should now be tested against orthodox management by controlled randomised trial.     

Prognosis of Node-Positive Breast Cancer Patients Who Underwent Parasternal Lymph Node Biopsy During Surgery Followed by Doxorubicin- or Mitoxantrone-Containing Adjuvant Chemotherapy

Abstract

The authors examined the survival rates of 60 patients with breast cancer who underwent parasternal lymph node biopsy during surgery with axillary lymph node dissection and had histologically confirmed axillary node metastasis followed by adjuvant doxorubicin- or mitoxantrone-containing combination chemotherapy to ascertain whether administration of anthracycline or its analogue improved the prognosis of both axillary and parasternal node-positive patients. The overall survival rate (OS) for the parasternal node-positive patients (n=13, 21.7%) was 30.6%, and relapse-free survival rate (RFS) fell to 0% at the 104-month follow-up. Although the survival rate for all axillary node-positive patients was similar to those in previous reports, the OS and RFS for both axillary and parasternal node-positive patients were significantly worse than that for axillary node-positive and parasternal node-negative patients, despite treatment with adjuvant doxorubicin- or mitoxantrone-containing combination chemotherapy. Other intensive adjuvant treatment strategies are needed to reduce distant metastases for high-risk breast cancer patients having both axillary and parasternal nodes positive.     

Prognostic significance of epidermal growth factor receptor in laryngeal squamous cell carcinoma.

Epidermal growth factor receptor (EGFR) content was determined by a radioligand receptor assay in 140 primary laryngeal squamous cell carcinomas (median value of 8.4 fmol mg-1 protein, range 0-169.9 fmol mg-1 protein). Cox univariate regression analysis using EGFR as a continuous variable showed that EGFR levels are directly associated with the risk of death (chi 2 = 14.56, P-value = 0.0001) and relapse (chi 2 = 7.77, P-value = 0.0053). A significant relationship between EGFR status and survival was observed at the different arbitrary cut-off values chosen (8, 16 and 20 fmol mg-1 protein). The cut-off value of 20 fmol mg-1 protein was the best prognostic discriminator. In fact, the 5 year survival was 81% for patients with EGFR- tumours compared with 25% for patients with EGFR+ tumours (P < 0.0001). The 5 year relapse-free survival was 77% for patients with EGFR- tumours compared with 24% for patients with EGFR+ tumours (P < 0.010). When clinicopathological parameters and EGFR status were examined in the multivariate analysis, T classification and EGFR status retained an independent prognostic value. In this study we demonstrated that high EGFR levels single out patients with poor prognosis in laryngeal cancer.     

EndoPredict predicts for the response to neoadjuvant chemotherapy in ER-positive,HER2-negative breast cancer

The EndoPredict (EP) signature is a prognostic 11-gene expression signature specifically developed in ER+/HER2– node-negative/positive breast cancer. It is associated with relapse-free survival in patients treated with adjuvant hormone therapy, suggesting that EP low-risk patients could be treated with adjuvant hormone therapy alone whereas high-risk patients would deserve addition of adjuvant chemotherapy. Thus, it is important to determine whether EP high-risk patients are or are not more sensitive to chemotherapy than low-risk patients. Here, we have assessed the EP predictive value for pathological complete response to neoadjuvant chemotherapy in ER+/HER2– breast cancer. We gathered gene expression and histoclinical data of 553 pre-treatment ER+/HER2– breast carcinomas treated with anthracycline-based neoadjuvant chemotherapy. We searched for correlation between the pathological complete response (pCR) and the EP score-based classification. The overall pCR rate was 12%. Fifty-one percent of samples were classified as low-risk according to the EP score and 49% as high-risk. EP classification was associated with a pCR rate of 7% in the low-risk group and 17% in the high-risk group (p < 0.001). In multivariate analysis, the EP score remained significantly associated with pCR. Many genes upregulated in the high-risk tumours were involved in cell proliferation, whereas many genes upregulated in the low-risk tumours were involved in ER-signalling and stroma. Despite higher chemosensitivity, the high-risk group was associated with worse disease-free survival. In conclusion, EP high-risk ER+/HER2– breast cancers are more likely to respond to anthracycline-based chemotherapy.     

The prognostic value of vascular endothelial growth factor in 574 node-negative breast cancer patients who did not receive adjuvant systemic therapy

The growth and metastasising capacity of solid tumours are dependent on angiogenesis. Vascular endothelial growth factor is a mediator of angiogenesis. In this study we investigated whether vascular endothelial growth factor is associated with the natural course of the disease in primary invasive breast cancer. In 574 tumours of patients with node-negative invasive breast cancer the cytosolic levels of vascular endothelial growth factor were measured using a quantitative enzyme-linked immunosorbent assay. These patients did not receive adjuvant systemic therapy and were followed for a median follow-up time of 61 months (range 2-155 months) after the primary diagnosis. Correlations with well-known prognostic factors, and univariate and multivariate survival analyses were performed. Vascular endothelial growth factor level was positively associated with age and tumour size (P=0.042 and P=0.029, respectively). In addition, vascular endothelial growth factor level was inversely, but weakly correlated with progesterone receptor levels (PgR) (r(s)=-0.090, P=0.035). A high vascular endothelial growth factor level (equal or above the median level of 0.53 ng mg(-1) protein) predicted a reduced relapse-free survival and overall survival in the univariate survival rate analysis (for both P=0.005). In the multivariate analysis as well, vascular endothelial growth factor showed to be an independent predictor of poor relapse-free survival and overall survival (P=0.045 and P=0.029, respectively), in addition to age, tumour size and PgR. The results show that cytosolic levels of vascular endothelial growth factor in tumour tissue samples are independently indicative of prognosis for patients with node-negative breast cancer who were not treated with adjuvant systemic therapy. This implies that vascular endothelial growth factor is related with the natural course of breast cancer progression.     

Epidermal growth factor receptor in lung malignancies. Comparison between cancer and normal tissue.

Epidermal growth factor receptors (EGFr) were measured using a radioligand binding assay, in membrane preparations from 51 human non-small cell lung cancers and in normal tissue of the same patients. The binding characteristics of EGFr were similar in tumour and normal lung membranes (range of dissociation constant of high affinity sites: 0.1-0.6 nM). However, the concentrations in tumours (median, 16.4 fmol mg-1 of protein; range, 1.5-176) were significantly higher than in normal tissues (median, 7.4 fmol mg-1 of protein; range, 1.9-13.4). The receptor levels in normal tissue were normally distributed. It was therefore possible to define a normal/pathologic cut-off level (12.9 fmol mg-1 of protein). In 57% of cases EGFr in cancer was higher than the cut-off. No relationships were found between receptor concentrations and positivity rates of EGFr and histology, stage, lymph node positivity and pT. A trend for a direct relation between receptor positivity and grading was found.