The purpose of this study was to classify breast carcinomas based on variations in gene expression patterns derived from cDNA microarrays and to correlate tumor characteristics to clinical outcome. A total of 85 cDNA microarray experiments representing 78 cancers, three fibroadenomas, and four normal breast tissues were analyzed by hierarchical clustering. As reported previously, the cancers could be classified into a basal epithelial-like group, an ERBB2-overexpressing group and a normal breast-like group based on variations in gene expression. A novel finding was that the previously characterized luminal epithelial/estrogen receptor-positive group could be divided into at least two subgroups, each with a distinctive expression profile. These subtypes proved to be reasonably robust by clustering using two different gene sets: first, a set of 456 cDNA clones previously selected to reflect intrinsic properties of the tumors and, second, a gene set that highly correlated with patient outcome. Survival analyses on a subcohort of patients with locally advanced breast cancer uniformly treated in a prospective study showed significantly different outcomes for the patients belonging to the various groups, including a poor prognosis for the basal-like subtype and a significant difference in outcome for the two estrogen receptor-positive groups.

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Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications

Breast cancer patients with the same stage of disease can have markedly different treatment responses and overall outcome. The strongest predictors for metastases (for example, lymph node status and histological grade) fail to classify accurately breast tumours according to their clinical behaviour. Chemotherapy or hormonal therapy reduces the risk of distant metastases by approximately one-third; however, 70-80% of patients receiving this treatment would have survived without it. None of the signatures of breast cancer gene expression reported to date allow for patient-tailored therapy strategies. Here we used DNA microarray analysis on primary breast tumours of 117 young patients, and applied supervised classification to identify a gene expression signature strongly predictive of a short interval to distant metastases ('poor prognosis' signature) in patients without tumour cells in local lymph nodes at diagnosis (lymph node negative). In addition, we established a signature that identifies tumours of BRCA1 carriers. The poor prognosis signature consists of genes regulating cell cycle, invasion, metastasis and angiogenesis. This gene expression profile will outperform all currently used clinical parameters in predicting disease outcome. Our findings provide a strategy to select patients who would benefit from adjuvant therapy.

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Gene expression profiling predicts clinical outcome of breast cancer

Background A more accurate means of prognostication in breast cancer will improve the selection of patients for adjuvant systemic therapy. Methods Using microarray analysis to evaluate our previously established 70-gene prognosis profile, we classified a series of 295 consecutive patients with primary breast carcinomas as having a gene-expression signature associated with either a poor prognosis or a good prognosis. All patients had stage I or II breast cancer and were younger than 53 years old; 151 had lymph-node–negative disease, and 144 had lymph-node–positive disease. We evaluated the predictive power of the prognosis profile using univariable and multivariable statistical analyses. Results Among the 295 patients, 180 had a poor-prognosis signature and 115 had a good-prognosis signature, and the mean (±SE) overall 10-year survival rates were 54.6±4.4 percent and 94.5±2.6 percent, respectively. At 10 years, the probability of remaining free of distant metastases was 50.6±4.5 percent in the group with a...

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A Gene-Expression Signature as a Predictor of Survival in Breast Cancer

background The likelihood of distant recurrence in patients with breast cancer who have no involved lymph nodes and estrogen-receptor–positive tumors is poorly defined by clinical and histopathological measures. methods We tested whether the results of a reverse-transcriptase–polymerase-chain-reaction (RT-PCR) assay of 21 prospectively selected genes in paraffin-embedded tumor tissue would correlate with the likelihood of distant recurrence in patients with node-negative, tamoxifen-treated breast cancer who were enrolled in the National Surgical Adjuvant Breast and Bowel Project clinical trial B-14. The levels of expression of 16 cancerrelated genes and 5 reference genes were used in a prospectively defined algorithm to calculate a recurrence score and to determine a risk group (low, intermediate, or high) for each patient. results Adequate RT-PCR profiles were obtained in 668 of 675 tumor blocks. The proportions of patients categorized as having a low, intermediate, or high risk by the RT-PCR assay were 51, 22, and 27 percent, respectively. The Kaplan–Meier estimates of the rates of distant recurrence at 10 years in the low-risk, intermediate-risk, and high-risk groups were 6.8 percent (95 percent confidence interval, 4.0 to 9.6), 14.3 percent (95 percent confidence interval, 8.3 to 20.3), and 30.5 percent (95 percent confidence interval, 23.6 to 37.4). The rate in the low-risk group was significantly lower than that in the high-risk group (P<0.001). In a multivariate Cox model, the recurrence score provided significant predictive power that was independent of age and tumor size (P<0.001). The recurrence score was also predictive of overall survival (P<0.001) and could be used as a continuous function to predict distant recurrence in individual patients. conclusions The recurrence score has been validated as quantifying the likelihood of distant recurrence in tamoxifen-treated patients with node-negative, estrogen-receptor–positive breast cancer.

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A Multigene Assay to Predict Recurrence of Tamoxifen-Treated, Node-Negative Breast Cancer

Morphological assessment of the degree of differentiation has been shown in numerous studies to provide useful prognostic information in breast cancer, but until recently histological grading has not been accepted as a routine procedure, mainly because of perceived problems with reproducibility and consistency. In the Nottingham/Tenovus Primary Breast Cancer Study the most commonly used method, described by Bloom & Richardson, has been modified in order to make the criteria more objective. The revised technique involves semiquantitative evaluation of three morphological features--the percentage of tubule formation, the degree of nuclear pleomorphism and an accurate mitotic count using a defined field area. A numerical scoring system is used and the overall grade is derived from a summation of individual scores for the three variables: three grades of differentiation are used. Since 1973, over 2200 patients with primary operable breast cancer have been entered into a study of multiple prognostic factors. Histological grade, assessed in 1831 patients, shows a very strong correlation with prognosis; patients with grade I tumours have a significantly better survival than those with grade II and III tumours (P less than 0.0001). These results demonstrate that this method for histological grading provides important prognostic information and, if the grading protocol is followed consistently, reproducible results can be obtained. Histological grade forms part of the multifactorial Nottingham prognostic index, together with tumour size and lymph node stage, which is used to stratify individual patients for appropriate therapy.

Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up.

Summary Macrophage colony production in vitro by bone marrow cells was studied at intervals after the implant of a syngeneic mammary tumor into C3H female mice. Between 4 days and 2 weeks of progressive tumor growth, there was a significantly increased production of macrophage colonies from the tumor-bearing animals when compared with three types of controls. After 2 weeks, the colony production returned to normal. The implications of this relative to the response of the host to tumor are discussed.

Macrophage production by the bone marrow of tumor-bearing mice.

During the past 15 to 20 years, there have resulted revolutionary changes in the local/regional management of primary breast cancer Why have those changes come about? Has science played a role or have they been entirely related to the experiences of a few who have “tampered with tradition” for some nebulous reason? This report traces the pathway of change from Halsted's time to the present and attempts to point out wherever possible the relation of these changes to science and/or to “anecdotalism” It traces the origins of the Halstedian hypothesis of cancer management, the reasons for its perpetuation, and the clinical challenges to it which were really not challenges at all A description of laboratory and clinical research in the 1960's which led to an alternative hypothesis is presented, as is a description of how clinical trials tested the alternative hypothesis The results of those trials, recently reported, lend support to a concept of surgery for cancer which embodies biological principles rather than the mechanistic and anatomical principles of the past A brief discussion is provided relative to how cancer surgery interrelates with other modalities and the article concludes with the author's concept of a surgical oncologist

The revolution in breast cancer surgery: science or anecdotalism?

There has been increasing interest regarding the use of Corynebacterium parvum (CP) with other modalities in the management of primary cancer. Due to the paucity of specific information available relative to CP toxicity, a Phase I study was carried out in patients with advanced disease. The purpose of the investigation was not to evaluate the effect of CP on tumor growth. from 273 injections of CP in 40 patients it was observed that following intravenous (i.v.) infusion of CP: a) a febrile response and chills of considerable severity occured in almost all patients and did not appreciably diminish in intensity following repetitive administrations; b) nausea, vomiting, headache, and confusion were not infrequent; c) a "flu-like" syndrome lasting 24 to 48 hours occurred following almost all courses of CP; d) blood pressure elevations occurred on occasion and were related to the severity of other-side-effects; hyper- or hypo- tension was not a problem; e) ther were no anaphalactic reactions. Pretreatment with a single administration of 100 mg of hydrocortisone prior to CP infusion markedly and in some instances dramatically diminished the toxicity and made acceptable the use of i.v. CP on an outpatient basis. The use of i.v. CP in patients with cerebral metasteses may be hazardous. Subcutaneously administered CP resulted in a significant number of undesirable local reactions. Evaluation of delayed cutaneous hypersensitivity response, immunoglobulins, complement, and E- and EAC-rosette-forming cells during CP administration failed to demonstrate significant change from injection values. Results were similar whether hydrocortisone pretreatment was or was not employed. From the standpoint of toxicity it now seems appropriate to use i.v. CP, particularly following pretreatment with hydrocortisone, in a controlled clinical trial to evaluate its therapeutic effectiveness in the management of primary cancer.

https://acsjournals.onlinelibrary.wiley.com/doi/epdf/10.1002/1097-0142%28197607%2938%3A1%3C119%3A%3AAID-CNCR2820380121%3E3.0.CO%3B2-1

Observations following Corynebacterium parvum administration to patients with advanced malignancy. A phase I study

SUMMARY Inconclusion: ● During the last two decades, as a result of the use of systemictherapy in conjunction with breast-conservation surgery andradiation therapy, the incidence of locoregional recurrencehas been reduced to a level where further reduction, a goalworthyofachieving,islikelytohavelittleimpactonsurvival. ● Despitetheextensiveinformationpresentedinthiscommen-tary, there is no new scientiﬁcally based evidence to justifyreplacing the current breast cancer hypothesis. ● It is likely that ﬁndings from research related to molecularbiologyandgeneticswillbethesourceofinformationthatwillresult in a new, testable thesis that will eventually replace thealternative hypothesis and thus the paradigm that currentlygoverns the treatment of breast cancer. Status of the Breast Cancer Hypothesis www.jco.org © 2009 by American Society of Clinical Oncology 373 Downloaded from jco.ascopubs.org on June 6, 2013. For personal use only. No other uses without permission.Copyright © 2010 American Society of Clinical Oncology. All rights reserved.

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The breast cancer alternative hypothesis: is there evidence to justify replacing it?

Summary There is evidence that the coagulation mechanism plays a role in the development of metastases and that anticoagulants, by interfering with the adherence of tumor cells to vascular endothelium, may impair secondary tumor growth. The present study, employing 51 Cr-labeled tumor cells in rats and rabbits, provided quantitative information relative to the effect of heparin, fibrinolysin, and the antifibrinolytic agent e-aminocaproic acid (EACA) on deposition and organ retention of such cells. It was observed: ( a ) that adequate continuous heparinization failed to promote the residence of tumor cells in the blood stream or to affect the lodgment of tumor cells in lung, liver, kidney, and spleen of rats from 1 hr to 7 days following the jugular vein injection of Walker tumor cells; ( b ) that the intraportal inoculation of Walker tumor cells resulted in similar retention of tumor cells in livers of heparinized and unheparinized rats; ( c ) that findings similar to those in the rat were noted following the jugular vein injection of V2 carcinoma cells in heparinized and fibrinolysin-treated rabbits; and ( d ) that EACA failed to affect the organ retention of tumor cells in the rabbit. It is concluded that anticoagulants do not influence metastases by preventing tumor cell lodgment and/or by promoting their residence within blood vessels. Other mechanisms to explain their effects on secondary tumor growth must be sought.

https://cancerres.aacrjournals.org/content/canres/27/2_Part_1/421.full.pdf

Bernard Fisher

Papers

Macrophage production by the bone marrow of tumor-bearing mice.

The revolution in breast cancer surgery: science or anecdotalism?

Observations following Corynebacterium parvum administration to patients with advanced malignancy. A phase I study

The breast cancer alternative hypothesis: is there evidence to justify replacing it?

Anticoagulants and Tumor Cell Lodgment