Betty G. Mobbs

Estrogen and progesterone receptor content of primary and secondary breast carcinoma: Influence of time and treatment

ER and PgR concentrations were assayed in primary and secondary breast carcinoma specimens from patients classified into 3 groups: (1) both specimens excised on the same occasion (61 patients); (2) specimens obtained on separate occasions with no intervening treatment (43 patients); (3) specimens obtained on separate occasions with intervening chemotherapy and/or irradiation (25 patients). There were highly significant linear correlations (P less than 0.001) between the concentrations of ER (expressed as log10) in primary and secondary specimens in all groups. The relationship between PgR concentrations in primary and secondary specimens in groups 1 and 2 was highly significant, although there appeared to be a greater tendency for loss of PgR in sequential, than in simultaneous secondary biopsies. When expressed in terms of hormone receptor status (HRS), the same rate of discordance was observed in groups 1 and 2 (30% when concentrations were expressed in terms of cytosol protein). In group 1 the major cause of discordance was the occurrence of receptor +ve secondaries in association with receptor -ve primaries, possibly because of the high cellularity of many involved axillary nodes. In group 2, the major cause of discordance was the occurrence of receptor -ve secondaries derived from receptor +ve primaries. In both groups discordance in PgR status was more frequent than in ER status. In group 3, overall discordance in HRS was 24% and was due equally to ER and PgR; however, the high concordance rate for PgR was probably due to the fact that the tumours were initially PgR -ve, and the secondaries were also -ve. These results confirm that ER content tends to be stable, even after long periods of time and the administration of chemotherapy and/or irradiation. Progesterone receptor content is much less stable, and may decrease during quite short time intervals even in the absence of treatment.

Prognostic factors affecting the natural history of node-negative breast cancer

Purpose. We undertook a natural history investigation of a broad selection of prognostic factors in a cohort of women with node-negative breast cancer.Patients and methods. The cohort consisted of 415 consecutive histologic node-negative (T1-3, M0) patients, operated on for primary breast cancer at Women’s College Hospital, Toronto, Canada, between 1977 and 1986. Only 7% of these patients were given adjuvant systemic therapy; further, for the 48% of women who underwent lumpectomy, only 29% received adjuvant radiotherapy to the breast. Paraffin-embedded tumour tissue was available for the majority of patients. The following factors were examined for their univariate and multivariate effects on time to recurrence outside the breast (DFI) and survival from breast cancer (DSS): age, weight, tumour size, estrogen receptor, progesterone receptor, histologic type, tumour grade, nuclear grade, lymphovascular invasion, overexpression of neu oncoprotein, DNA ploidy, % cells in S-phase, and adjuvant therapy. Multivariate analyses utilized a Cox model with a step-wise factor selection for the 260 patients with complete information.Results. A worse prognosis was indicated when there was lymphovascular invasion (for DFI, p<0.001; for DSS, p=0.0046), high %S-phase (for DFI, p=0.08; for DSS, p=0.02), high tumour grade (for DFI, p=0.02; for DSS, p=0.03), and overexpression of neu oncoprotein (for DSS, p=0.07).Conclusions. In our natural history investigation, two factors, lymphovascular invasion and tumour grade, are of particular interest since they may be readily incorporated into clinical practice. Overexpression of neu oncoprotein may also play a role in determining prognosis for women administered adjuvant systemic therapy.

A comparison of all-subset Cox and accelerated failure time models with Cox step-wise regression for node-positive breast cancer

SummaryClinical studies usually employ Cox step-wise regression for multivariate investigations of prognostic factors. However, commercial packages now allow the consideration of accelerated failure time models (exponential, Weibull, log logistic, and log normal), if the underlying Cox assumption of proportional hazards is inappropriate. All-subset regressions are feasible for all these models.We studied a group of 378 node positive primary breast cancer patients accrued at the Henrietta Banting Breast Centre of Womens College Hospital, University of Toronto, between January 1, 1977, and December 31, 1986. 85% of these patients had complete prognostic factor data for multivariate analysis, and 96% of the patients were followed to 1990. There was evidence of marked departures from the proportional hazards assumption with two prognostic factors, number of positive nodes and adjuvant systemic therapy. The data strongly supported the log normal model. The all-subset regressions indicated that three models were similarly good. The variables 1) number of positive nodes, 2) tumour size, and 3) adjuvant systemic therapy were included in all three models along with one of three biochemical receptor variables 1) ER, 2) combined receptor (ER- PgR-; ER+ PgR-; ER- PgR+; ER+ PgR+; or 3) PgR.Better multivariate modeling was achieved by using quantitative prognostic factors, a check for appropriate underlying model-type, and all-subset variable selection. All-subset regressions should be considered for routine use with the many new prognostic factors currently under evaluation; it is very possible that there may not be a single model that is substantially better than others with the same number of variables.

Ascertaining Prognosis for Breast Cancer in Node‐Negative Patients with Innovative Survival Analysis

Abstract:  Clinical decisions to administer adjuvant systemic therapy to women with early breast cancer require knowledge about baseline prognosis, which is only assessable in the absence of such adjuvant treatment, which most patients currently do receive. The Cox model is the standard tool for assessing the effect of prognostic factors; however, there may be substantive differences in the estimated prognosis obtained by the Cox model rather than a log‐normal model. For more than 50 years, clinical breast cancer data for cohorts of patients have supported the choice of a log‐normal model. The prognostic impact of model type is examined here for a cohort of breast cancer patients, only 7% of whom received adjuvant systemic therapy. We quantitated prognosis utilizing Kaplan–Meier, Cox, and log‐normal survival analyses for 415 consecutive T1–T3, M0, histologically node‐negative patients who were operated on for primary breast cancer at Womens College Hospital between 1977 and 1986. Recurrence outside the breast for disease‐free interval (DFI) and breast cancer death for disease‐specific survival (DSS) were the events of interest. The patient follow‐up for these investigations was 96% complete: a median 8 years for those surviving. Factors used in these investigations were age, weight, tumor size, histology, tumor grade, nuclear grade, lymphovascular invasion, estrogen receptor (ER), progesterone receptor (PR), combined ER/PR receptor, overexpression of neu oncoprotein, DNA ploidy, S‐phase, and adjuvant therapy. In our study we found evidence against the Cox assumption of proportional hazards, which is not an assumption for the log‐normal approach. We identified patients with greater than 96% and others with less than 40% DSS at 10 years. The difference in prognosis determined by using the Cox versus the log‐normal model ranged for DFI from 1.2% to 8.1%, and for DSS from 0.4% to 6.2%; interestingly, the difference was more substantial for patients with a high risk of recurrence or death from breast cancer. Estimated prognoses may differ substantially by survival analysis model type, by amounts that might affect patient management, and we think that the log‐normal model has a major advantage over the Cox model for survival analysis.

An investigation of cut-points for primary breast cancer oestrogen and progesterone receptor assays

Oestrogen and progesterone receptor (ER and PgR) assay values are frequently used in medical decision-making for breast cancer patients. We have proposed statistical standardization of receptor assay values to improve inter-laboratory comparability, and now report the use of standardized log units (SLU) to investigate the effects of ER and PgR cut-points on time to first recurrence outside the breast (DFS). Between 1980 and 1986, there were 678 primary breast cancer patients treated at the Henrietta Banting Breast Centre (HBBC). The effects of ER and PgR cut-points were examined with multivariate analyses considering the variables: age, tumour size, nodal status, weight and adjuvant treatment. We considered receptor assay cut-points ranging from - 1.0 to + 1.0 SLU (ER between 7 and 166 fmol/mg protein; PgR between 7 and 181 fmol/mg protein). PgR was included in the multivariate prognostic models more often than ER, although patients had a better prognosis with both larger ER and PgR values. There was no best cut-point for ER or PgR, and there was strong evidence that ER and PgR should be considered as continuous rather than dichotomous (negative, positive) variables. Patient prognosis should also be more comparable with SLU.

The Henrietta Banting Breast Centre database : a model for clinical research utilizing a hospital-based inception cohort

The cohort study design has been used successfully in clinical cancer research. Cohorts, however, are valuable only if they produce results which are valid and generalizable. Some hospital-based inception cohorts satisfy both these requirements and may thus be useful research tools. The development of one such hospital-based cohort, the Henrietta Banting Breast Centre database, is described. This cohort is composed of 1097 women diagnosed with primary breast cancer at Womens College Hospital, Toronto, from January 1977 through December 1986. Details of diagnostic procedures, pathology, treatment, dates and sites of recurrence, and date of death are available on 96% of women. By comparison with published series and with the Ontario Cancer Registry, we have demonstrated validity and generalizability. A major advantage is the ready availability of paraffin tissue blocks on virtually all cases, facilitating analyses of the prognostic importance of specific biologic variables and immunocytochemical hormone assays. Other completed studies and future uses of the cohort are described.

The standardization of estrogen receptors

Tumour estrogen receptor (ER) status may determine the medical treatment of a patient with breast cancer; yet inter-laboratory results can vary markedly, particularly when absolute cut-offs in fmol/mg cytosol protein are used. The use of standardized log units is proposed to permit greater inter-laboratory comparability. We have assessed the biochemical ER values using the dextran-coated charcoal method with three data sets, two quality control (QC) sets for Ontario laboratories and a data set with values for 184 primary breast cancer patients seen at Womens College Hospital (WCH) between 1985 and 1986. The distributions for all the raw data were skewed toward the lower end of the range; a log transformation improved the symmetry of the distributions. There was marked inter-laboratory variation in the QC data, and standardized log units greatly reduced this variability. The WCH data had similar differentiation by tumour size and nodal status with both the raw data and standardized log units. However, standardized log units provided more consistent evidence of an association between ER and immunohistochemical ERICA. The standardized log units provide quantitative receptor values suitable for multi-centre research, for future work with clinical outcomes, and for the daily management of patients.

Tamoxifen and Metastatic Breast Cancer

Excerpt To the editor: A recent article by Legha, Davis, and Muggia (Ann Intern Med88:69-77, 1978) documents the effectiveness of tamoxifen in postmenopausal women with metastatic breast cancer but...

Hormonal responsiveness of prostatic carcinoma: in vitro technique for prediction.

Abstract An attempt to establish an in vitro technique to assist in selecting the most appropriate therapy for patients with prostatic carcinoma is presented.

Synkavit Radios en sitizing agent in prostatic carcinoma

Abstract Six male cynomolgus monkeys were intravenously injected with 10 microcuries per pound of tritiated synkavit and 0.67 mg. per pound of carrier synkavit. Two animals were sacrificed at fifteen minutes, two at thirty minutes, and two at one hour after injection. Samples of caudal prostate, bladder, testis, spleen, liver, lung, upper and lower intestines, skin, muscle, fat, urine, and serum were removed. At fifteen minutes the concentration of menadione in the prostate gland was 2.26 × 10 −6 M, which is more than that found in any other tissue. This level is sufficient for radiosensitization.