A three-stage genome-wide association study recently identified single nucleotide polymorphisms (SNPs) in five loci (fibroblast growth receptor 2 (FGFR2), trinucleotide repeat containing 9 (TNRC9), mitogen-activated protein kinase 3 K1 (MAP3K1), 8q24, and lymphocyte-specific protein 1 (LSP1)) associated with breast cancer risk. We investigated whether the associations between these SNPs and breast cancer risk varied by clinically important tumor characteristics in up to 23,039 invasive breast cancer cases and 26,273 controls from 20 studies. We also evaluated their influence on overall survival in 13,527 cases from 13 studies. All participants were of European or Asian origin. rs2981582 in FGFR2 was more strongly related to ER-positive (per-allele OR (95%CI) = 1.31 (1.27–1.36)) than ER-negative (1.08 (1.03–1.14)) disease (P for heterogeneity = 10−13). This SNP was also more strongly related to PR-positive, low grade and node positive tumors (P = 10−5, 10−8, 0.013, respectively). The association for rs13281615 in 8q24 was stronger for ER-positive, PR-positive, and low grade tumors (P = 0.001, 0.011 and 10−4, respectively). The differences in the associations between SNPs in FGFR2 and 8q24 and risk by ER and grade remained significant after permutation adjustment for multiple comparisons and after adjustment for other tumor characteristics. Three SNPs (rs2981582, rs3803662, and rs889312) showed weak but significant associations with ER-negative disease, the strongest association being for rs3803662 in TNRC9 (1.14 (1.09–1.21)). rs13281615 in 8q24 was associated with an improvement in survival after diagnosis (per-allele HR = 0.90 (0.83–0.97). The association was attenuated and non-significant after adjusting for known prognostic factors. Our findings show that common genetic variants influence the pathological subtype of breast cancer and provide further support for the hypothesis that ER-positive and ER-negative disease are biologically distinct. Understanding the etiologic heterogeneity of breast cancer may ultimately result in improvements in prevention, early detection, and treatment.

Chronic pain was more common after breast-conserving surgery than after radical surgery. Surgical complications and postoperative radiotherapy and chemotherapy increased the risk of chronic pain and other symptoms. Modifications in the treatment protocol and preclusion of postoperative complications may be necessary in order to minimize chronic treatment-related symptoms.

Summary This study assessed pain, neurological symptoms, oedema of the ipsilateral arm, anxiety and depression occurring in women treated surgically for breast cancer, the impact of these symptoms on daily life and how they evolved during the 1 year follow-up. Ninety-three consecutive patients with non-metastasised breast cancer who were treated during 1993 -94 were examined before surgery and after 1, 6 and 12 months. They were asked about pain, neurological symptoms and oedema in the breast scar region and/or ipsilateral arm. Sensory testing was performed, and gripping force and the circumference of the arm were measured. Anxiety and depression were evaluated. One year after surgery, 80% of the women had treatment-related symptoms in the breast scar region and virtually all patients had symptoms in the ipsilateral arm. The incidence of chronic post-treatment pain was higher after conservative surgery than after radical surgery (breast area: 33% vs 17%, NS; ipsilateral arm: 23% vs 13%, NS). Numbness occurred in 75% and oedema of the ipsilateral arm in over 30% of the patients after both radical and conservative surgery. Phantom sensations in the breast were reported by 25% of the patients. No difference in psychic morbidity was detected after the two types of surgery. Both the anxiety and depression scores were highest before surgery, decreasing with time, and were significantly correlated with preoperative stressful events.Keywords: breast cancer; breast surgery; chronic pain; quality of life Several recent studies (Rayter et al., 1990;Kuusk et al., 1992;Fisher et al., 1995) found no significant differences in the overall or disease-free survival between patients treated with either total mastectomy or breast-conserving surgery with breast radiation. However, follow-up studies indicate that some women suffer from various chronic treatment-related symptoms such as pain, sensory disturbances, oedema and muscle weakness, the reported incidence of which varies from 5 to 74% (Olsen et al., 1993;Thompson et al., 1995). Recently, Stevens et al. (1995) reported a 20% prevalence rate of the post-surgical pain syndrome in 95 women after breast surgery. The incidence of chronic pain did not differ statistically significantly after mastectomy compared with lumpectomy. In our recent retrospective study, in which 467 women completed a questionnaire on post-treatment symptoms 10-58 months after surgery, pain, paraesthesiae or strange sensations were reported by half of the patients. These chronic treatment-related symptoms were more common after breast resection (BCT) than after modified radical mastectomy (MRM) (Tasmuth et al., 1995). The incidence of pain in the operated breast area after both types of surgery and in the ipsilateral arm after MRM was higher if less time had elapsed since surgery. About 25% of the patients in this study reported chronic pain that affected their daily lives at least moderately.A few studies have examined the time course of various post-treatment symptoms following treatment of breast cancer...

NQO1 guards against oxidative stress and carcinogenesis and stabilizes p53. We find that a homozygous common missense variant (NQO1(*)2, rs1800566(T), NM_000903.2:c.558C>T) that disables NQO1 strongly predicts poor survival among two independent series of women with breast cancer (P = 0.002, N = 1,005; P = 0.005, N = 1,162), an effect particularly evident after anthracycline-based adjuvant chemotherapy with epirubicin (P = 7.52 x 10(-6)) and in p53-aberrant tumors (P = 6.15 x 10(-5)). Survival after metastasis was reduced among NQO1(*)2 homozygotes, further implicating NQO1 deficiency in cancer progression and treatment resistance. Consistently, response to epirubicin was impaired in NQO1(*)2-homozygous breast carcinoma cells in vitro, reflecting both p53-linked and p53-independent roles of NQO1. We propose a model of defective anthracycline response in NQO1-deficient breast tumors, along with increased genomic instability promoted by elevated reactive oxygen species (ROS), and suggest that the NQO1 genotype is a prognostic and predictive marker for breast cancer.

Purpose: The p53 R72P polymorphism has been suggested to play a role in many cancers, including breast cancer. Our aim was to evaluate association of R72P with breast cancer risk as well as histopathologic features of the breast tumors and survival. Experimental Design: The germ line R72P genotype was defined among 939 Finnish familial and 888 unselected breast cancer patients and 736 healthy population controls. The clinical and biological variables were tested for association by univariate analysis and the effects of several variables on survival by Cox's proportional hazards regression model. Results: The distribution of the genotypes was similar in all groups studied, suggesting no association with breast cancer risk. Unselected breast cancer patients with 72P homozygous genotype presented significantly more often with lobular carcinoma, whereas R72 allele carriers had a significantly higher frequency of ductal carcinomas (P = 0.004). No significant association with other histopathologic variables, like tumor grade, hormone receptor status (estrogen and progesterone receptors), or tumor-node-metastasis stage, was observed. Survival analysis showed that unselected breast cancer patients with 72P homozygous genotype had significantly poorer survival than patients with other genotypes (P = 0.003). This effect on survival was independent of p53 expression in the tumors and multivariate analysis showed that 72P homozygous genotype was overall an independent prognostic factor (risk ratio of death, 2.1; 95% confidence interval, 1.4-3.3; P = 0.001). Conclusions: These results suggest no effect of either R72P allele on breast cancer risk but a significantly reduced survival for 72P homozygous breast cancer patients. The finding of codon 72 genotype as an independent prognostic marker for breast cancer warrants further studies.

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Although the outgrowth of micrometastases into macrometastases is the rate-limiting step in metastatic progression and the main determinant of cancer fatality, the molecular mechanisms involved have been little studied. Here, we compared the gene expression profiles of melanoma lymph node micro- and macrometastases and unexpectedly found no common up-regulation of any single growth factor/cytokine, except for the cytokine-like SPP1. Importantly, metastatic outgrowth was found to be consistently associated with activation of the transforming growth factor-beta signaling pathway (confirmed by phospho-SMAD2 staining) and concerted up-regulation of POSTN, FN1, COL-I, and VCAN genes-all inducible by transforming growth factor-beta. The encoded extracellular matrix proteins were found to together form intricate fibrillar networks around tumor cell nests in melanoma and breast cancer metastases from various organs. Functional analyses suggested that these newly synthesized protein networks regulate adhesion, migration, and growth of tumor cells, fibroblasts, and endothelial cells. POSTN acted as an anti-adhesive molecule counteracting the adhesive functions of FN1 and COL-I. Further, cellular FN and POSTN were specifically overexpressed in the newly forming/formed tumor blood vessels. Transforming growth factor-beta receptors and the metastasis-related matrix proteins, POSTN and FN1, in particular, may thus provide attractive targets for development of new therapies against disseminated melanoma, breast cancer, and possibly other tumors, by affecting key processes of metastasis: tumor/stromal cell migration, growth, and angiogenesis.

The risk of remarkable long-time arm morbidity after SNB is minimal. Work-related events seem uncommon due to arm morbidity, regardless of the extent of axillary surgery.