Stewart Nicholson

Relationship between c-erbB-2 protein product expression and response to endocrine therapy in advanced breast cancer.

Of 221 patients with breast cancer of known epidermal growth factor receptor (EGFR) and oestrogen receptor (ER) status, 99 had developed recurrences during the period of follow-up (range 3-60 months, median 24 months). Of these, 72 received endocrine therapy as first-line treatment for relapse. Immunohistochemical assessment of c-erbB-2 protein product expression was made using paraffin-embedded tumour tissue from 65 of these 72 patients. Including patients whose disease remained stable for more than 6 months with those showing an objective response (CR or PR for more than 3 months), only one (7%) of 14 c-erbB-2 positive tumours responded to endocrine manipulation compared with 19 (37%) of 51 c-erbB-2 negative tumours (P less than 0.05). Coexpression of c-erbB-2 reduced the response rate of ER positive patients from 48% to 20% and of ER negative cases from 27% to 0% (P less than 0.01). EGFR and c-erbB-2 protein appeared to have additive effects in reducing the likelihood of response, and none of eight patients with EGFR positive, c-erbB-2 positive tumours derived benefit from endocrine therapy. The results of this study suggest that c-erbB-2 protein overexpression, a marker of poor prognosis in breast cancer, is associated with a lack of response to endocrine therapy on relapse, and particularly in combination with EGFR may be useful in directing therapeutic choices.

EXPRESSION OF EPIDERMAL GROWTH FACTOR RECEPTORS ASSOCIATED WITH LACK OF RESPONSE TO ENDOCRINE THERAPY IN RECURRENT BREAST CANCER

Epidermal growth factor receptors (EGFR) and oestrogen receptors (ER) were analysed in 221 patients with primary operable breast cancer by means of radioligand assays. After median follow-up of 24 months (range 3-60 months), there had been recurrences in 99 patients, of whom 72 (median age 56 years, range 32-77 years) received tamoxifen alone as first-line treatment for recurrence. 20 patients (28%) showed a response to this therapy and 52 (72%) did not. Of 32 ER-positive tumours, 12 (37.5%) showed an objective response to tamoxifen compared with only 2 of 40 (5%) ER-negative tumours (p less than 0.005). Of 35 EGFR-positive tumours, 3 (8.5%) achieved an objective response compared with 11 of 37 (30%) EGFR-negative tumours (p less than 0.05). Only 1 of 28 EGFR-positive, ER-negative tumours achieved an objective response. Including patients whose disease remained stable for more than 6 months with the responders, however, EGFR status was a better predictor of response to tamoxifen; 15 of 37 EGFR-negative patients and 5 of 35 EGFR-positive patients responded (p less than 0.01), compared with 13 of 32 ER-positive and 7 of 40 ER-negative patients (not significant). EGFR expression is a highly significant marker of poor prognosis in patients with breast cancer; it appears to be as good a predictor as ER for objective response and better for overall response to endocrine therapy on relapse.

Epidermal growth factor receptors in breast cancer: Association with early relapse and death, poor response to hormones and interactions with neu

Epidermal growth factor receptors (EGFRs) were measured in 221 primary breast cancers by ligand binding with 125I-labelled EGF, and high-affinity sites were quantitated. There was a highly significant inverse relationship between oestrogen receptor (ER) and EGFR (15 EGFR-positive [EGFR+]ER+ and 92 EGFR-negative [EGFR-]ER+: 54 EGFR- ER- and 60 EGFR+ ER-). The relapse-free survival and overall survival were significantly shorter for EGFR+ vs EGFR- tumours (P less than 0.001) by about 2 yr in the case of relapse-free survival. When ER- tumours were substratified by EGFR status, the EGFR- ER- tumours had a prognosis almost as good as the ER+ tumours. In 31 of 184 cases, high expression of neu, correlating with amplification, was found. Expression of neu conferred similar poor prognosis to EGFR expression in all prognostic subgroups. Coexpression of neu and EGFR had an additive adverse effect. Epidermal growth factor receptors (EGFR) and oestrogen receptors (ER) were analysed in 221 patients with primary operable breast cancer by means of radioligand assays. After median follow-up of 24 months (range 3-60 months), there had been recurrences in 99 patients, of whom 72 (median age 56 yr, range 32-77 yr) received tamoxifen alone as first-line treatment for recurrence. 14 patients (19%) showed a response to this therapy and 58 (81%) did not. Of 32 ER+ tumours, 12 (37.5%) showed an objective response to tamoxifen compared with only 2 of 40 (5%) ER- tumours (P less than 0.005). Of 35 EGFR+ tumours, 3 (8.5%) achieved an objective response compared with 11 of 36 (30%) EGFR tumours (P less than 0.05). Only 1 of 28 EGFR+, ER- tumours achieved an objective response. Including patients whose disease remained stable for more than 6 months with the responders, however, EGFR status was a better predictor of response to tamoxifen; 15 of 37 EGFR- patients and 5 of 35 EGFR+ patients responded (P less than 0.01).

EPIDERMAL GROWTH-FACTOR RECEPTOR (EGFR) AS A MARKER FOR POOR PROGNOSIS IN NODE-NEGATIVE BREAST-CANCER PATIENTS - NEU AND TAMOXIFEN FAILURE

Analysis of EGFr and ER was performed on tumour samples from 231 patients with operable breast cancer followed for up to 6 yr 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 tumours greater than 10 fmol/mg 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 0.00001). EGFr was second only to axillary node status as a prognostic marker for all patients both in terms of relapse-free and overall survival (P less than 0.001, logrank EGFr+ vs EGFr-). For patients with histologically negative axillary nodes EGFr was superior to ER in predicting relapse and survival (P less than 0.01 and P less than 0.005, respectively, compared to P less than 0.1 and P less than 0.1, logrank). 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 = 0.052 and P = 0.026, respectively). The correlation of neu expression with response to tamoxifen in patients with recurrent disease was assessed immunochemically. Response rate was reduced in the presence of neu from 50 to 17% for ER+ cases and from 26 to 0% for ER- cases.

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.

Epidermal growth factor receptor status of histological sub-types of breast cancer

The histological breakdown of a consecutive series of 264 surgically resected malignant lesions of the breast was studied. Oestrogen and epidermal growth factor receptor status was quantified and presented along with size and lymph node status of the non-ductal lesions. Those non-ductal tumours containing EGF receptors have all recurred within two years of resection. Twenty-one percent of the lobular carcinomas contained EGF receptors compared to 34% of ductal carcinomas. EGF receptor status appeared to be associated with an increased risk of early recurrence and death whatever the histological sub-type of the breast cancer.

Epidermal growth factor receptors in human breast cancer

Epidermal Growth Factor (EGF) is a small (6045 Dalton) protein that stimulates cell proliferation in both cell culture systems and in intact animals. EGF was first isolated from the submaxillary gland of the mouse by Cohen in 1962 [1]. Extracts of the gland when injected into newborn animals induced precocious eyelid opening and incisor eruption. At the time, Cohen was involved in research on Nerve Growth Factor but realized the potential importance of a substance with such profound biological effects. The biological response to injection of extracts of the submaxillary gland was due to a stimulation of epidermal growth and keratinization. The factor responsible for these effects was named Epidermal Growth Factor. The mouse EGF molecule contains 53 amino acid residues [2] and has disulphide bonds between cysteine residues 5 and 20, 14 and 31, 33 and 42, producing three disulphide loops in the secondary structure [3]. Mouse EGF is produced from a much larger precursor molecular of 130,000 Daltons [4]. In the mid 1970s, EGF was detected [5] and isolated from human urine [6]. In 1975 Gregory demonstrated that human EGF was equivalent to urogastrone, a hormone capable of inhibiting gastric acid secretion. Mouse EGF and urogastrone (Uro-EGF) share a 70% homology but are antigenically distinct as shown by radioimmunoassay [7]. They are, however, interchangeable in radioligand assays and growth stimulatory experiments.