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

In females of both spontaneously and induced ovulating species, pheromones from male conspecifics can directly stimulate GnRH neuronal activity, thereby inducing pituitary LH secretion and stimulating the onset of estrus. However, whether pheromones contribute to the steroid- or mating-induced preovulatory activation of GnRH neurons is less clear. Previous studies in the ferret, an induced ovulator, raised the possibility that olfactory cues contribute to the ability of genital-somatosensory stimulation to activate GnRH neurons in the mediobasal hypothalamus (MBH). In the present study the percentage of GnRH neurons colabeled with Fos-immunoreactivity (IR), used as a marker for neuronal activation, was investigated in the MBH of mated gonadectomized, estradiol-treated female ferrets in which both nares were occluded. In addition, the percentage of GnRH neurons colabeled with Fos-IR was examined in the MBH of gonadectomized, estradiol-treated female ferrets exposed to male bedding. Bilateral nares occlusion successfully blocked mating or odor-induced increments in Fos-IR in central olfactory regions, including the cortical and medial amygdala. By contrast, the percentage of GnRH neurons expressing Fos-IR did not differ between mated nares- and sham-occluded females. Exposure to male bedding alone failed to induce Fos-IR in MBH GnRH neurons. Thus, the mating-induced preovulatory activation of GnRH neurons in the female ferret's MBH appears to rely solely on genital-somatosensory as opposed to olfactory inputs.

https://bioone.org/journals/Biology-of-Reproduction/volume-64/issue-4/biolreprod64.4.1100/Mating-Induces-Gonadotropin-Releasing-Hormone-Neuronal-Activation-in-Anosmic-Female/10.1095/biolreprod64.4.1100.pdf

Mating Induces Gonadotropin-Releasing Hormone Neuronal Activation in Anosmic Female Ferrets

From a study of the organization of a national clinical trial on the management of early cancer of the breast in women there appear to be overwhelming advantages in studying large numbers of patients. To this end centres abroad have been encouraged to join. All the evidence at present suggests that it is feasible to organize a study on this scale, that the documentation and follow-up are accurate, and that the enthusiasm of the participants can be successfully fostered and maintained.

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Organization of Clinical Trial on National Scale: Management of Early Cancer of the Breast

Evidence is reviewed suggesting that ovarian steriods modulate the expression by female primates of behavior that increases the likelihood of copulation (proceptivity), in addition to affecting females' sexual attractivity. Data often cited as showing that circulating androgens regulate sexual proceptivity and receptivity in female primates are critically reviewed. The essential interaction of social and endocrine factors in the control of female primates' sexual activity is emphasized. Accepted for publication 19 March 1983)

Hormonal Modulation of Sexuality in Female Primates

Ovohysterectomized female ferrets were housed in controlled environment rooms in which the daily lighting schedule was either 15L:9D (long days) or 9L:15D (short days). After 2 weeks some ferrets in each group were given an intrajugular catheter: beginning 1 week later, a blood sample was taken daily at one of eight different clock times over an 8 to 10 day period. One additional blood sample plus the pineal gland were collected from these animals and from uncathetarized animals in each group after decapitation at different clock times. Both plasma melatonin concentrations and pineal melatonin content were elevated in a square-wave pattern during the dark hours, with the duration of elevation being longer in ferrets kept under the short days. These results suggest that differences in the duration of nocturnal increments in melatonin secretion may mediate the stimulatory and inhibitory effects of long and short days, respectively, on ovarian activity in female ferrets.

Plasma and pineal melatonin levels in female ferrets housed under long or short photoperiods.

Despite millions of pounds spent on breast cancer research, a major breakthrough in terms of curing the disease still eludes us. Last year over 24500 women in the UK were newly diagnosed as having breast cancer and 15 000 women died from it. Thus it remains the biggest killer of western women in their middle years. Although these facts paint a somewhat gloomy picture, there have been some dramatic changes recently in the management ofthe disease. These are likely to improve considerably the quality of life, without necessarily adding to the length of life, for those women unfortunate enough to require breast cancer treatment. One change, highlighted in the paper by Morris et al. (this issue, p 12), concerns the clear shift towards more conservative surgical procedures a trend likely to continue at a rapid pace as more encouraging results emerge from clinical trials throughout the world. Some women who still have to undergo mastectomy for technical reasons are however benefiting from better cosmesis, both in breast reconstruction techniques and the materials used for these and external prostheses. Another improvement in management has occurred with the advent of effective, non-toxic adjuvant therapy such as Tamoxifen. Trials are also in progress to establish whether or not Tamoxifen alone can be used with confidence to treat elderly breast cancer patients, thus saving them from the perils ofsurgery. The role of cytotoxic chemotherapy in breast cancer remains a controversial issue but the perceived need for aggressive treatment with high doses of distressingly toxic agents is receding, in this country at least. The past decade has also seen refinements in the techniques of radiation therapy which are undoubtedly quicker and safer than previously. A further major area ofbeneficial change in breast cancer management concerns the psychological wellbeing of patients. There has been an increasing awareness by health professionals ofthe psychosocial havoc provoked by the disease and its treatment. Several enlightened hospitals now provide a liaison psychiatry service such as the one described by Ramirez (this issue, p 15). Others have spialist nurses in their breast clinics to provide counselling and prosthesis fitting. We have important data emerging from studies suggesting that the way in which the surgeon conducts the 'bad news' consultation, i.e. informing the patient ofthe diagnosis and treatment options, can have a major impact on short and longterm psychological outcome. In particular, the way in which different surgeons discuss the choice of treatment appears to be an interesting variable. Two small studies have suggested that women who are permitted some choice oftreatment wherever possible, display a more positive psychological adjustment than those offered no choicel2. We await the results from a large prospective study of 300 patients to see ifthese apparent benefits are maintained even when women develop a recurrence of their disease3. It is important to emphasize that merely preserving a woman's breast does not guarantee protection from psychological and sexual dysfunction4. Patients who avoid the disfigurement of mutilating surgery nevertheless still have to contend with the fact that they have had cancer. Our own research has shown that women treated by conservative surgery still have many unmet psychological needs5. Fortunately there are ways to ameliorate some of the distress caused by a diagnosis of breast cancer and its treatment. We offer below 10 guidelines based on current knowledge which given good will and resources, should substantially improve the quality of life for women with breast cancer.

http://jrs.sagepub.com/content/82/1/4.full.pdf

Michael J. Baum

Papers

Mating Induces Gonadotropin-Releasing Hormone Neuronal Activation in Anosmic Female Ferrets

Organization of Clinical Trial on National Scale: Management of Early Cancer of the Breast

Hormonal Modulation of Sexuality in Female Primates

Plasma and pineal melatonin levels in female ferrets housed under long or short photoperiods.

Psychological welfare of patients with breast cancer.