Systematic review and meta-analysis

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 finding of a decrease in contralateral breast cancer incidence following tamoxifen administration for adjuvant therapy led to the concept that the drug might play a role in breast cancer prevention. To test this hypothesis, the National Surgical Adjuvant Breast and Bowel Project initiated the Breast Cancer Prevention Trial (P-1) in 1992. Methods: Women (N = 13 388) at increased risk for breast cancer because they 1) were 60 years of age or older, 2) were 35‐59 years of age with a 5-year predicted risk for breast cancer of at least 1.66%, or 3) had a history of lobular carcinoma in situ were randomly assigned to receive placebo (n = 6707) or 20 mg/day tamoxifen (n = 6681) for 5 years. Gail’s algorithm, based on a multivariate logistic regression model using combinations of risk factors, was used to estimate the probability (risk) of occurrence of breast cancer over time. Results: Tamoxifen reduced the risk of invasive breast cancer by 49% (two-sided P<.00001), with cumulative incidence through 69 months of follow-up of 43.4 versus 22.0 per 1000 women in the placebo and tamoxifen groups, respectively. The decreased risk occurred in women aged 49 years or younger (44%), 50‐59 years (51%), and 60 years or older (55%); risk was also reduced in women with a history of lobular carcinoma in situ (56%) or atypical hyperplasia (86%) and in those with any category of predicted 5-year risk. Tamoxifen reduced the risk of noninvasive breast cancer by 50% (two-sided P<.002). Tamoxifen reduced the occurrence of estrogen receptor-positive tumors by 69%, but no difference in the occurrence of estrogen receptor-negative tumors was seen. Tamoxifen administration did not alter the average annual rate of ischemic heart disease; however, a reduction in hip, radius (Colles’), and spine fractures was observed. The rate of endometrial cancer was increased in the tamoxifen group (risk ratio = 2.53; 95% confidence interval = 1.35‐4.97); this increased risk occurred predominantly in women aged 50 years or older. All endometrial cancers in the tamoxifen group were stage I (localized disease); no endometrial cancer deaths have occurred in this group. No liver cancers or increase in colon, rectal, ovarian, or other tumors was observed in the tamoxifen group. The rates of stroke, pulmonary embolism, and deep-vein thrombosis were elevated in the tamoxifen group; these events occurred more frequently in women aged 50 years or older. Conclusions: Tamoxifen decreases the incidence of invasive and noninvasive breast cancer. Despite side effects resulting from administration of tamoxifen, its use as a breast cancer preventive agent is appropriate in many women at increased risk for the disease. [J Natl Cancer Inst 1998;90:1371‐88]

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Tamoxifen for Prevention of Breast Cancer: Report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study

Background We present the combined results of two trials that compared adjuvant chemotherapy with or without concurrent trastuzumab in women with surgically removed HER2-positive breast cancer. Methods The National Surgical Adjuvant Breast and Bowel Project trial B-31 compared doxorubicin and cyclophosphamide followed by paclitaxel every 3 weeks (group 1) with the same regimen plus 52 weeks of trastuzumab beginning with the first dose of paclitaxel (group 2). The North Central Cancer Treatment Group trial N9831 compared three regimens: doxorubicin and cyclophosphamide followed by weekly paclitaxel (group A), the same regimen followed by 52 weeks of trastuzumab after paclitaxel (group B), and the same regimen plus 52 weeks of trastuzumab initiated concomitantly with paclitaxel (group C). The studies were amended to include a joint analysis comparing groups 1 and A (the control group) with groups 2 and C (the trastuzumab group). Group B was excluded because trastuzumab was not given concurrently with paclit...

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Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer

EDITOR—In 1987, while I was professor of surgery at King's College London, I was given the task of establishing the first mammographic screening unit in southeast England. This followed the findings of the Forrest committee that were announced by Margaret Thatcher two weeks before a general election. My colleagues from the radiology department and I took great pride in setting up a purpose built unit at Camberwell Green, and within a year of receiving our instructions we were up and running and serving as the …

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Ramifications of screening for breast cancer: Consent for screening

Current and future management of "early" breast cancer: attitude survey amongst participants in cancer research campaign trial

Relyingprimarilyon indirectputative indicesof fetal testosterone (T) exposure (2D:4Ddigit ratios and otoacoustic emissions), Breedlove (2017) summarizes literature supporting the conclusionthat lesbianwomen,onaverage,areexposedtogreaterprenatal androgen than are straight women. By contrast, Breedlove argues that homosexual orientation inmen (based on these same putativeretrospectivemarkersof fetalandrogenaction)cannotbe easily explainedbya reduction inprenatal androgen. Instead, Breedlove suggests that there may be, as yet unidentified, brainspecific reductions in response to androgen in male fetuses who grow up to be gay. Breedlove argues persuasively that the nonhuman animal literature on the critical role of perinatal testosterone exposure in forming male-typical forebrain and/or spinal cord nuclear volume, neuronal number, and neuronal phenotype remainsthebedrockreasonforsuspectingthat theremustbesome link between fetal and/or early postnatal variations in circulating testosterone’s neural actions and adult sexual orientation in humans.He points out that in the few documented human examples of sex differences in brain and spinal cord neuronal morphology, thesizeof thesexdifferencesneverapproachthemagnitude of the homologous morphological sex differences seen in several rodent species aswell as ferrets andsheep.Breedlovealso alludestothelargeanimalliteratureonsexdifferencesinbehavior (usually without specifying types of behavior), saying: ‘‘Having spentmostofmyadult life investigatingsexdifferences inbehavior innon-humananimals,Ihavewonderedwhethertheresults of animal studies have any relevance to sex differences in human behavior.’’ In so far as the topic of Breedlove’s article concerns prenatal influences on human sexual orientation,wewere surprised that he barely mentions a sizable animal literature on the hormonal and neuralcontrolofmale-typical,aswellas female-typical, sexual partner preference. The single such animal study cited (Roselli, Larkin, Resko, Stellflug, & Stormshak, 2004) described the interesting correlative observation that a minority (*8% of the population screened) of male sheep (rams), when given a choice betweenmountinganestrouseweoranotherram,showedahomosexual preference and chose to mount the ram. The volume of a sexually dimorphic nucleus (ovine SDN) located at the border of themedial preoptic area/anterior hypothalamus (mPOA/AH)was significantly greater in heterosexual (gynephilic) rams than in ewes.Bycontrast, thevolumeof theSDNinandrophilic (homosexual) rams was significantly lower than in gynephilic rams, although its volumewas still significantly greater than the SDN of ewes. AsBreedlovepointsout, ithasbeendifficult toestablisheithera correlational or a causal linkage between observed sex dimorphisms in forebrain nuclear volume and the capacity of male and femaleanimals todisplaymatingoranyother typeofsocialbehavior. This is especially true if one restricts the analysis to themotor patternsassociatedwithmalecopulation.Thus, forexample,when given testosterone inadulthood,gonadectomized female, like male, rats display all of the features ofmale-typical copulation (mounts, intromission-like behaviors, ejaculation-like behaviors) in testswithanestrousfemale(Emery&Sachs,1975).Yet, there is a striking twofold–threefold difference (male greater than female) in the dimensions of theSDNnucleus in the rat POA/AH(Gorski, Gordon, Shryne,&Southam, 1978)—abrain region that has long been linked to the display of male copulation in numerous vertebrate species (Hull, Meisel, & Sachs, 2002). There is also disagreement in the literature (Arendash & Gorski, 1983; de Jonge & Michael J. Baum baum@bu.edu

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Reconsidering Prenatal Hormonal Influences on Human Sexual Orientation: Lessons from Animal Research.

Current controversies in the role of antioestrogens in the treatment of carcinoma of the breast

https://bjssjournals.onlinelibrary.wiley.com/doi/pdf/10.1002/bjs.1800750344

Michael J. Baum

Papers

Ramifications of screening for breast cancer: Consent for screening

Current and future management of "early" breast cancer: attitude survey amongst participants in cancer research campaign trial

Reconsidering Prenatal Hormonal Influences on Human Sexual Orientation: Lessons from Animal Research.

Current controversies in the role of antioestrogens in the treatment of carcinoma of the breast

Pain scores in haemorrhoidectomy.