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

A sexually dimorphic male nucleus (MN) is present in Nissl-stained sections through the dorsal (d) preoptic area/anterior hypothalamus (POA/AH) of male ferrets. The MN-POA/AH is composed of a cluster of large cells which is organized in males by the action of estradiol, formed via the neural aromatization of circulating testosterone (T), during the last quarter of a 41-day gestation. Several recent studies using rodent species have raised the possibility that the hormone-induced masculinization of POA/AH morphology is mediated at least in part by a perinatal modulation of cell death. We asked whether a perinatal reduction in cell death contributes to the differentiation of the MN-POA/AH in the male ferret, which is a carnivore species. The appearance of internucleosomal DNA fragmentation, detected by in situ end labeling (ISEL) using the ApopTag kit (Oncor Corp.) and of pyknotic cell nuclei in Nissl-stained sections were used to estimate the occurrence of cell death. Male and female ferret kits were killed at four different ages spanning the perinatal period during which the MN-POA/AH is organized and assumes an adult phenotype. A peak density of dying cells was present in both sexes at postnatal day (P) 2, which is nearly 1 week after the age, embryonic day (E) 37, when the MN-POA/AH is first visible in male ferrets using Nissl stains. The density of cells in the sexually dimorphic dPOA/AH which were either ISEL-positive or pyknotic was similar in males and females on E34, as well as on P2, 10, and 20. In the nondimorphic ventral POA/AH, the highest density of dying cells was present in both sexes at E34, and there were significantly more ISEL-positive cells present in males than females at this particular age. In contrast to previous studies using rodents, our results suggest that in fetal male ferrets a modulation of the incidence of cell death contributes little to estradiol's organizational action in the dPOA/AH.

Cell death in the sexually dimorphic dorsal preoptic area/anterior hypothalamus of perinatal male and female ferrets

Administration of the serotonin (5-HT)1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) facilitates the expression of masculine sexual behavior in male and female rats as well as in male rhesus monkeys and inhibits lordosis behavior in female rats. In the present study the effects of 8-OH-DPAT on masculine coital and feminine proceptive and receptive behaviors were evaluated in the ferret, a carnivore. Doses of 8-OH-DPAT (0.1 or 0.2 mg/kg) that facilitate masculine sexual behavior in rats inhibited masculine sexual behavior in castrated, estradiol benzoate (EB)-treated male ferrets. Lower doses of 8-OH-DPAT (5 or 10 µg/kg) had no effect on the expression of masculine sexual behavior in either males or females. In contrast to the female rat, administration of 8-OH-DPAT significantly facilitated receptive behaviors in ovariectomized, EB-treated female ferrets. None of the doses of 8-OH-DPAT tested modified proceptive behaviors of gonadectomized, EB-treated male or female ferrets, as assessed in a T-maze in which the subjects could choose to approach either a castrated, sexually inactive male or a castrated, testosterone-primed stud male. Thus whereas the 5-HT1A receptor agonist 8-OH-DPAT facilitates masculine sexual behavior and inhibits lordosis in the rat, it inhibits masculine sexual behavior and facilitates receptivity in the ferret. The different effects of 8-OH-DPAT observed in these two species may reflect differences in the neural control of their masculine coital and feminine receptive responses, respectively.

Differential effects of the serotonin1A agonist, 8-OH-DPAT, on masculine and feminine sexual behavior of the ferret

Gonadal hormones, but not sex, affect the acquisition and maintenance of a Go/No-Go odor discrimination task in mice.

The ferret is a reflex-ovulating species in which receipt of an intromission induces a prolonged (±12 h) preovulatory LH surge in the estrous female. This LH surge is probably stimulated by a large release of GnRH from the mediobasal hypothalamus (MBH). In Exp 1 we asked whether GnRH messenger RNA (mRNA) levels increase in response to mating so as to replenish the MBH GnRH stores needed to sustain the preovulatory LH surge. Estrous females were killed 0, 0.25, 0.5, 1, 3, 6, 14, or 24 h after the onset of a 10-min intromission from a male. Coronal brain sections ranging from the rostral preoptic area caudally to the posterior hypothalamus were processed for in situ hybridization using a 35S-labeled oligoprobe complementary to the human GnRH-coding region. We found no evidence of increased MBH GnRH mRNA levels during the ferret’s mating-induced preovulatory LH surge. Instead, the number of GnRH mRNA-expressing cells dropped significantly in the arcuate region beginning 6 h after onset of intromission and re...

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Changes in mediobasal hypothalamic gonadotropin-releasing hormone messenger ribonucleic acid levels induced by mating or ovariectomy in a reflex ovulator, the ferret.

EDITOR,—We applaud E Lidbrink and colleagues' attempts to quantify the substantial disadvantages of false positive findings in patients invited to attend for breast screening.1 Clearly, a financial cost of over £250000 from a single round of screening at a well organised centre in Stockholm represents a huge sum …

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Michael J. Baum

Papers

Cell death in the sexually dimorphic dorsal preoptic area/anterior hypothalamus of perinatal male and female ferrets

Differential effects of the serotonin1A agonist, 8-OH-DPAT, on masculine and feminine sexual behavior of the ferret

Gonadal hormones, but not sex, affect the acquisition and maintenance of a Go/No-Go odor discrimination task in mice.

Changes in mediobasal hypothalamic gonadotropin-releasing hormone messenger ribonucleic acid levels induced by mating or ovariectomy in a reflex ovulator, the ferret.

False positive findings of mammography will have psychological consequences.