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Biomedical subjects

Yasuo Miyoshi

Publications and source records attributed to Yasuo Miyoshi.

At least 37 records · Page 2Linked to original sources

Prognostic significance of intra-tumoral estradiol level in breast cancer patients.

Although the intra-tumoral estradiol (E2) level is thought to be more closely related to the E2-inducible events such as progesterone receptor (PR) induction and tumor growth than the serum E2 level, prognostic significance of the intra-tumoral E2 level in breast cancer patients has yet to be studied. E2 level in tumor tissues obtained from 90 primary breast cancer patients were measured by the high-pressure liquid chromatography-radioimmunoassay method. Relationship between the intra-tumoral E2 level and the various clinicopathological factors including the prognosis was investigated. E2-high tumors (n=45) were significantly more likely to be estrogen receptor (ER)-positive tumors and PR-positive tumors than E2-low tumors (n=45). A significant correlation was observed between the intra-tumoral E2 level and PR level by a simple curve fit test (r=0.39, P<0.01) in the ER-positive tumors. Univariate analysis showed that lymph node status, intra-tumoral E2 level, ER, and PR were significant prognostic factors, and multivariate analysis showed that only lymph node status and PR status were significant independent prognostic factors. PR is induced by E2 through ER in human breast cancers. PR, which warrants both the presence of functional ER and the enough level of intra-tumoral E2, can serve as a better prognostic factor than intra-tumoral E2 level or ER in primary breast cancer patients probably because PR is a better marker of estrogen-dependency of tumor growth than intra-tumoral E2 level or ER.

Adult↗

Association of p53 genetic polymorphism (Arg72Pro) with estrogen receptor positive breast cancer risk in Japanese women.

Since it is well established that inactivation of p53 is involved in pathogenesis of breast cancer, it seems to be reasonable to assume that p53 genetic polymorphism at codon 72 (p53Arg72Pro) which affects the function of p53 might have an influence on breast cancer risk. Thus, in the present study, we have studied the association of p53Arg72Pro polymorphism with breast cancer risk. A case-control study was conducted with 191 breast cancer patients and 218 healthy female controls. p53Arg72Pro polymorphism was examined in their association with breast cancer risk after adjustment for the epidemiological risk factors. Relationship between p53Arg72Pro polymorphism and clinicopathological characteristics of breast cancers was also studied. In addition, frequency of somatic p53 mutation was compared according to the genotype of p53Arg72Pro polymorphism. p5372Pro/Pro homozygotes showed a significant increase in the risk of estrogen receptor (ER) positive breast cancer (adjusted odds ratio (OR) = 2.04, P = 0.04) as compared with p5372Arg/Arg homozygotes, whereas such an association was not found between p5372Pro/Pro homozygotes and ER negative breast cancer risk. Subset analysis according to menopausal status showed that p5372Pro/Pro homozygotes were significantly associated with ER positive breast cancer risk in postmenopausal women (adjusted OR = 3.42, P = 0.01) but not in premenopausal women. Frequency of ER positive tumors was significantly (p < 0.01) higher in breast cancer patients with p5372Pro/Pro genotype (82.8%) than those with p5372Arg/Arg genotype (54.5%). Mutational analysis of p53 in tumors showed that p5372Pro/Pro homozygotes had a lower frequency of p53 mutation (3.5%) than p5372Arg/Arg homozygotes (10.5%). It is suggested that p53Arg72Pro polymorphism is associated with ER positive breast cancer risk, especially, in postmenopausal women. The higher frequency of p53 somatic mutation in p5372Arg/Arg homozygotes than p5372Pro/Pro homozygotes is consistent with the thesis that the function of p5372Pro/Pro is impaired so that a further alteration of p53 gene is less required in p5372Pro/Pro homozygotes than p5372Arg/Arg homozygotes.

Adult↗

NY-ESO-1 expression and immunogenicity in malignant and benign breast tumors.

NY-ESO-1 is a cancer/testis antigen expressed in normal adult tissues solely in the testicular germ cells of normal adults and in various cancers. It induces specific humoral and cellular immunity in patients with NY-ESO-1-expressing cancer. The aim of this study was to determine the frequency of NY-ESO-1 mRNA and protein expression in malignant and benign breast tumors. NY-ESO-1 mRNA expression was detected by conventional reverse transcription-PCR and real-time PCR, and that of the protein expression by immunohistochemistry and Western blot analysis. Expression of NY-ESO-1 mRNA was detected in 37 of 88 (42%) cancer specimens, whereas that of the NY-ESO-1 protein was detected only in 1 mRNA-positive specimen. In the latter case, expression level of NY-ESO-1 mRNA relative to that in the testis was relatively high (75% of testicular expression) and to the other among breast cancer specimens. In benign breast lesions, 21 of 31 (68%) specimens expressed low levels of NY-ESO-1 mRNA. In 1 case of fibroadenoma, NY-ESO-1 mRNA was 8% of the testicular level, and protein was detected by Western blot analysis. Only 1 breast cancer patient had detectable antibody at time of surgery, which disappeared within 2 years. Tumor specimen from this patient was both NY-ESO-1 mRNA and protein positive, and NY-ESO-1-specific CD8 T cells were detected in this patient by IFN-gamma enzyme-linked immunospot assay using NY-ESO-1 recombinant adeno and vaccinia virus. A higher rate of NY-ESO-1 expression was noted in breast cancer with high histological grade and negative hormone receptor status, suggesting NY-ESO-1 as a potential tumor antigen for immunotherapy in patients with breast cancer and poor prognosis.

Adenoviridae↗

Absence of mutations in the Wilms' tumor gene WT1 in primary breast cancer.

BACKGROUND: It was recently demonstrated that the WT1 gene was overexpressed in primary breast cancer and that the high expression levels of WT1 mRNA significantly correlated with poor prognosis. However, it remained undetermined whether or not the WT1 gene expressed in breast cancer had mutations. METHODS: Breast cancer tissues were obtained from 36 patients with breast cancer. WT1 genomic DNA was PCR-amplified and examined for mutations by direct sequencing. RESULTS: The sequencing analysis showed the absence of mutations through the whole 10 exons of the WT1 gene in the 36 cases of primary breast cancer. Two different single nucleotide polymorphisms (SNP) without an amino acid change (Pro42, C to T in exon 1, and/or Arg300, A to G in exon 7) were detected in the WT1 gene in 31 (86%) of the 36 cases examined. CONCLUSION: The results indicate that the wild-type WT1 gene plays an important role in the tumorigenesis of primary breast cancer.

Adult↗

mRNA expression level of estrogen-inducible gene, alpha 1-antichymotrypsin, is a predictor of early tumor recurrence in patients with invasive breast cancers.

We previously identified 18 genes that correlated with ER positivity by adapter-tagged competitive-PCR analysis of 2412 genes in human breast cancer tissues. The aim of the present study was to determine the prognostic significance of these genes. mRNA expression levels of 12 of the above 18 genes were quantified in breast cancer tissues by real-time PCR assay, and their association with patients' prognosis (n = 110) was studied according to hormone receptor (HR) status. In addition, the genes found to influence prognosis were further investigated to examine whether their mRNA expression could be induced by estrogen in MCF-7 cells in vitro. Of the 12 genes, mRNA expression levels of two [alpha 1-antichymotrypsin (ACT) and stanniocalcin 2 (STC2)] were significantly (P = 0.002 and P = 0.007, respectively) associated with good prognosis in HR-positive (ER and/or PR positive) breast cancer patients treated with adjuvant hormone therapy. Multivariate analysis showed that ACT mRNA level, but not STC2 mRNA level, in HR-positive patients, was a significant prognostic factor (P = 0.042), which was independent of tumor size and lymph node metastases. On the other hand, mRNA expressions of ACT and STC2 were not significantly associated with prognosis in HR-negative patients. Estradiol treatment resulted in a significant increase in the mRNA levels of both ACT and STC2 in MCF-7 cells. The mRNA level of ACT, which is an estrogen-inducible gene, is a significant predictor of good prognosis in HR-positive, but not HR-negative, patients with breast cancers. Since HR-positive patients were treated with adjuvant hormone therapy, we suggest that ACT mRNA level could potentially be used as a predictor of response to hormone therapy, rather than a prognostic factor (predictor of metastatic potential).

Breast Neoplasms↗

Association of serum adiponectin levels with breast cancer risk.

PURPOSE: Adiponectin is a peptide hormone secreted from the adipose tissue, affecting the proliferation and insulin sensitivity of various types of cells. Because association of obesity with breast cancer risk is well established, it is possible that adiponectin plays some role in the development of breast cancer. Thus, in the present study, the association of the serum adiponectin levels with breast cancer risk was investigated. EXPERIMENTAL DESIGN: A case-control study was conducted on 102 breast cancer patients (cases) and 100 healthy women (controls). The serum adiponectin levels of cases and controls were examined in their association with breast cancer risk after adjustment for the various classical risk factors (family history, age at menarche, parity, body mass index, and so forth). In addition, the relationship between the serum adiponectin levels and the various clinicopathological characteristics of breast cancers was studied. RESULTS: Women in the low tertile of serum adiponectin levels were associated with a significantly (P < 0.005) increased risk for breast cancer compared with women in the high tertile [odds ratio (OR), 3.63; 95% confidence interval (CI), 1.61-8.19]. Such an association was observed both in the premenopausal women (OR, 3.46; 95% CI, 0.89-13.50) and in the postmenopausal women (OR, 3.90; 95% CI, 1.23-12.44). The frequency of large (>2 cm) tumors and that of high histological grade (2+3) tumors were significantly (P < 0.005 and P < 0.05, respectively) higher in breast cancer patients in the low tertile of the serum adiponectin levels than those in the high and intermediate tertiles. CONCLUSIONS: These results suggest that the low serum adiponectin levels are significantly associated with an increased risk for breast cancer and that tumors arising in women with the low serum adiponectin levels are more likely to show a biologically aggressive phenotype. The association between obesity and breast cancer risk might be partly explained by adiponectin.

Adiponectin↗

Mutational analysis of BARD1 in familial breast cancer patients in Japan.

Since BRCA1,which is a breast cancer susceptibility gene, form heterodimers with BARD1, it is speculated that BARD1 mutations might affect the function of BRCA1, contributing to breast carcinogenesis. Thus, in the present study, we have conducted mutational analysis of BARD1 in familial breast cancer patients (n=60) who were tested negative for both BRCA1 and BRCA2 germline mutations. We have been unable to show any clearly deleterious mutations but identified four missence mutations (Ser/Cys 241, Arg/Ser 378, Asn/Ser 470, Val/Met 507), one silent mutation (His/His 506), and one frameshift (in-frame) mutation (1139del21bp). Of these six mutations, one (Asn/Ser 470) was considered as a putative germline mutation since such a mutation was not observed in any of the healthy controls (n=152) but the other five mutations were considered as common genetic polymorphisms since they were frequently observed in the healthy controls. These genetic polymorphisms were further analyzed in their association with breast cancer risk by a case-control study using the population-based breast cancers (n=143) and healthy controls (n=155), which showed that carriers of the variant allele Met at codon 507 are significantly associated with the increased risk of breast cancer (adjusted odds ratio=2.05, 95% confidential interval=1.01-4.16) in postmenopausal women and that the other genetic polymorphisms are not associated with breast cancer risk. These results suggest that BARD1 mutations are responsible for, if any, a very small number of familial breast cancers. Genetic polymorphism of BARD1 (Val/Met 507) could be useful in the selection of postmenopausal women at a high risk for developing breast cancer.

Breast Neoplasms↗

Prediction of response to docetaxel by quantitative analysis of class I and III beta-tubulin isotype mRNA expression in human breast cancers.

PURPOSE: The relationship of intratumoral mRNA levels of class I and III beta-tubulin isotypes with clinical response to docetaxel has been studied in breast cancer patients. EXPERIMENTAL DESIGN: Expression of class I and class III beta-tubulin mRNA levels was determined by a real-time PCR in breast cancer tissues obtained from 39 patients with locally advanced breast cancers (n = 26) or locally recurrent breast cancers (n = 13) before docetaxel treatment. RESULTS: Class I beta-tubulin mRNA levels of responders [6.58 +/- 1.43 (x10(2)), mean +/- SE] were significantly (P = 0.002) lower than those of nonresponders [14.97 +/- 2.95 (x10(2))], and class III beta-tubulin mRNA levels of responders (1.38 +/- 0.40) were also significantly (P = 0.003) lower than those of nonresponders (7.43 +/- 2.77). Breast cancers were divided into four groups according to the expression status of class I and class III beta-tubulin isotype mRNA, i.e., the class I-high/class III-high group (n = 13), the class I-high/class III-low group (n = 7), the class I-low/class III-high group (n = 7), and the class I-low/class III-low group (n = 12). The class I-high/class III-high group showed a very low response rate (15%), whereas the class I-low/class III-low group showed a very high response rate (75%). The class I-high/class III-low group and the class I-low/class III-high group showed intermediate response rates of 57% and 43%, respectively. CONCLUSIONS: These results demonstrate that high expression of class I and class III beta-tubulin isotype mRNA is significantly associated with docetaxel resistance, and determination of class I and class III beta-tubulin isotype mRNA levels would be useful in the prediction of response to docetaxel.

Adult↗

Association of CYP17 genetic polymorphism with intra-tumoral estradiol concentrations but not with CYP17 messenger RNA levels in breast cancer tissue.

The variant allele(1931C) of CYP17 (1931C/T), which is one of the key enzymes involved in estrogens synthesis, has been shown to be associated with breast cancer risk. Since this variant allele creates an additional putative Sp-1 binding site (CCACC) in the promoter region, it is speculated that it enhances the transcription of CYP17, leading to the enhanced estrogens synthesis in breast tumors. CYP17 messenger RNA (mRNA) expression could be detected in all the normal breast (n=51) and tumor tissues (n=67) by a real-time polymerase chain reaction but CYP17 mRNA expression was not significantly different between the variant allele carriers and non-carriers. In addition, no significant correlation was observed between CYP17 mRNA and E2 levels in tumors, indicating an unimportant role of CYP17 in in situ synthesis of E2. On the other hand, intra-tumoral E2 levels were significantly (P=0.025) higher in the variant allele carriers (127.2+/-11.0 pg/g) than non-carriers (88.2+/-8.5 pg/g). Since it has been previously reported that serum E2 levels are higher in variant allele carriers than non-carriers, it is speculated that the higher intra-tumoral E2 levels in the variant allele carriers might be ascribed to the higher serum E2 levels.

Adult↗

Current status of endocrine therapy for breast cancer.

Endocrine therapy is usually indicated prior to chemotherapy as the first line therapy for metastatic breast cancer patients because of its milder toxicity. Patients who respond to a first-line endocrine therapy have a high chance of responding to a second-line endocrine therapy, and thus the responders to a first-line endocrine therapy would better be treated with second or third-line endocrine therapy. In the adjuvant setting, tamoxifen (antiestrogen) has been proven to improve the prognosis of both pre- and postmenopausal estrogen receptor positive breast cancer patients, and goserelin (LH-RH agonist) has been proven to improve prognosis in premenopausal women comparable to chemotherapy (CMF). Very recently, preliminary results have indicated that anastrozole (aromatase inhibitor) is superior to tamoxifen as adjuvant treatment for estrogen receptor positive postmenopausal breast cancer patients. In addition, the recent success of tamoxifen in a chemoprevention trial seems to have ushered in a new era wherein prevention of breast cancer is much more emphasized than treatment of established breast cancer.

Algorithms↗

Absence of beta-tubulin gene mutation in gastric carcinoma.

BACKGROUND: Effective chemotherapy for advanced gastric cancer is yet to be established. Taxanes, novel anticancer drugs which bind to beta-tubulin and prevent disruption of microtubules, are newly approved and promising agents for advanced and recurrent gastric cancer. To predict the chemoresistance to a taxan in gastric cancer, we examined the genetic mutations of the beta-tubulin gene. METHODS: Fifty pairs of gastric tumor and normal mucosa tissues were obtained from operations and the genomic DNA was extracted from each specimen. The four exons of the beta-tubulin gene were amplified for DNA mutations by single-strand conformation polymorphism (SSCP) methods and sequencing analysis. RESULTS: Nine (18%) of 50 patients with gastric cancer had two kinds of silent variations of the beta-tubulin gene in exon 4. Three kinds of intronic variations were detected in exons 1, 2, and 3. However, no genetic alterations that would change the beta-tubulin protein structure were detected in any of the 50 gastric tumors. CONCLUSION: Our findings indicate that mutations of the beta-tubulin gene, which might be a contraindication for chemotherapy based on taxans, were very rare events in gastric cancer.

Aged↗

Polymorphisms of estrogen synthesizing and metabolizing genes and breast cancer risk in Japanese women.

Recent success of chemoprevention with tamoxifen has opened a new era wherein prevention of breast cancer is much more emphasized than treatment of established breast cancer. Since tamoxifen has been shown to reduce the risk of estrogen receptor (ER)-positive, but not ER-negative, breast cancer in the chemoprevention trial (P-1), it seems to be important to develop risk factors for ER-positive breast cancer in order to select the candidates for chemoprevention more appropriately. Estrogens, the major risk factors for breast cancer, are speculated to affect breast cancer risk through ER, thus, genetic polymorphisms of the genes involved in the estrogens biosynthesis and metabolism are expected as risk factors for ER-positive breast cancer. Significance of polymorphisms of the genes involved in estrogens biosynthesis (CYP17, CYP19) and metabolism (CYP1A1, CYP1B1, COMT) in modulating the susceptibility to breast cancer is reviewed. The ethnic difference of the variant allele frequencies between Caucasian women and Asian women is also discussed.

Aromatase↗

Increased expression of BRCA1 mRNA predicts favorable response to anthracycline-containing chemotherapy in breast cancers.

Clinical significance of BRCA1 and BRCA2 mRNA levels in tumor tissues as predictors of response to anthracycline-containing chemotherapy was studied in breast cancer patients. Fifty-one patients with locally advanced breast tumors (n = 43) or locally recurrent tumors (n = 8) underwent tumor biopsy and were treated with CE (cyclophosphamide (600 mg/m2) plus epirubicin (60 mg/m2), q3w). BRCA1 and BRCA2 mRNA levels in the tumors were determined by a real-time PCR assay, and the expression of p53 and erbB2 in tumors was determined by immunohistochemistry. BRCA1 mRNA levels (1.317 +/- 0.277, mean +/- S.E.) of responders were significantly (p < 0.05) higher than those (0.609 +/- 0.097) of non-responders but there was no significant difference in BRCA2 mRNA levels between responders (1.590 +/- 0.326) and non-responders (1.586 +/- 0.410). Tumors were dichotomized into the BRCA1 mRNA levels high and low group according to the cut-off value of 0.55. Response rate (65%) of tumors with high BRCA1 mRNA levels was significantly (p < 0.05) higher than that (32%) of tumors with low BRCA1 mRNA levels. There was no significant association between response to CE and the expression of p53 or erbB2. Positive predictive value, negative predictive value, and diagnostic accuracy of BRCA1 mRNA determination in the prediction of response to CE were 65, 68, and 67%, respectively. These results suggest a possibility that BRCA1 mRNA levels in tumor tissues might be useful in the prediction of response to CE treatment in breast cancer patients.

Antibiotics, Antineoplastic↗

Overexpression of the Wilms' tumor gene WT1 in primary thyroid cancer.

The expression levels of the Wilms' tumor gene WT1 were examined in 34 primary thyroid cancers (24 papillary, 5 follicular, 1 anaplastic, and 4 medullary carcinomas), 17 thyroid follicular adenomas, and 6 normal-appearing thyroid tissues using quantitative real-time reverse transcriptase-polymerase chain reaction (RT-PCR). In 33 of 34 thyroid cancers, the WT1 mRNA was expressed at levels ranging from 5.0 x 10 (-5) to 8.3 x 10 (-2) levels (WT1 expression level in K562 leukemic cells was defined as 1.0). The WT1 mRNA expression levels were significantly higher than those in either thyroid follicular adenomas (P < 0.001) or normal-appearing thyroid tissues (P < 0.01). Immunohistochemical analysis confirmed the expression of WT1 protein in 20 of 21 thyroid cancers with WT1 mRNA expression. WT1 protein was also detected in 6 of 7 follicular adenomas with WT1 mRNA expression. However, the intensity of staining of WT1 protein in adenoma cells was weaker than that in cancer cells and its expression was restricted to approximately 30-80% of adenoma cells in the tumors examined. The direct sequencing analysis of the WT1 genomic DNA showed no mutations in any of the 10 exons of the WT1 gene in all of the 9 different thyroid cancers. These findings indicate an important role of the wild-type WT1 gene in the tumorigenesis of primary thyroid cancer.

Adenocarcinoma, Follicular↗

Aromatase inhibitors for treatment of postmenopausal patients with breast cancer.

The third generation of aromatase inhibitors and inactivators, such as anastrozole (Arimidex), letrozole (Femara) and exemestane (Aromasin), have become available for treatment of postmenopausal breast cancer patients. Several clinical trials have demonstrated that these new drugs can achieve better treatment results than megestrol acetate (Megace) and may replace tamoxifen for the first-line hormonal therapy for metastatic breast cancer patients. In fact, these drugs are now used in many hospitals and clinics for patients with metastatic breast cancer who were previously given tamoxifen as adjuvant treatment. However, the primary concern is whether they can be used as first-line agents for adjuvant treatment of primary breast cancer or are suitable for breast cancer prevention in view of possible adverse side effects. Recently, the Arimidex and Tamoxifen Alone or in Combination trial demonstrated the superiority in terms of disease-free survival of anastrozole over tamoxifen in adjuvant use for postmenopausal patients with Stage I and II primary breast cancer. The results of this report indicate the potential of anastrozole as an alternative drug in the adjuvant setting, although the mean follow-up time is so far only 47 months. Additional data regarding survival resulting from comparative trials of letrozole and tamoxifen and of exemestane and tamoxifen are expected to be available in a few years. However, limited information is available regarding adverse events caused by long-term administration of aromatase inhibitors. Longer follow-up is needed to determine the efficacy and safety of these new aromatase inhibitors when used for adjuvant treatment of postmenopausal patients with breast cancer.

Antineoplastic Agents↗

[A case of metastatic pheochromocytoma with remarkable response to combination of cyclophosphamide, vincristine and dacarbazine].

We report the case of a 58-year-old man with metastatic tumors 13 months after the initial surgery for paraganglioma at the left adrenal gland. A CT scan revealed a large tumor at the right scapula and abdominal paraaortic lymph nodes, and the patient received combination therapy of cyclophosphamide, vincristine and dacarbazine (CVD) every 3 to 4 weeks. After 11 courses, the serum catecholamine level was reduced to the normal range. The metastatic tumors showed optimal reduction in size, and the patient remains alive with no symptoms of the disease one year after the primary chemotherapy. The combination therapy of cyclophosphamide, vincristine and dacarbazine is considered a feasible and effective chemotherapy for metastatic malignant pheochromocytoma.

Adrenal Gland Neoplasms↗

Association of BRCA2 polymorphism at codon 784 (Met/Val) with breast cancer risk and prognosis.

PURPOSE: The association of BRCA2 polymorphisms at codon 372 [Asn (N)/His (H)]and codon 784 [Met (M)/Val (V)] with breast cancer risk was evaluated in Japanese women. In addition, the prognostic significance of these polymorphisms was studied in breast cancer patients. EXPERIMENTAL DESIGN: A case-control study was conducted to examine the association of the BRCA2 N/H372 polymorphism and M/V 784 polymorphism with breast cancer risk (cases = 149, controls = 154). The prognostic significance of these polymorphisms was evaluated in 139 patients with primary breast cancer. RESULTS: No significant association was observed between the N/H372 polymorphism and breast cancer risk. In contrast, a significant increase in breast cancer risk (odds ratio, 2.03; 95% confidence interval, 1.07-3.87) was observed in carriers of the variant allele (V784) of the M/V784 polymorphism as compared with noncarriers after adjustment for the classical risk factors, age, family history, parity, body mass index, and so forth. Among breast cancer patients, various clinicopathological parameters including menopausal status, tumor size, lymph node status, histological grade, and estrogen-receptor status were not significantly different between the carriers and noncarriers of the variant allele with regard to both N/H372 and M/V784 polymorphisms. The N/H 372 polymorphism was not significantly associated with patient prognosis. On the other hand, breast cancer patients carrying the variant allele of M/V784 polymorphism showed a significantly (P = 0.014) lower 3-year disease-free survival rate (63%) than noncarriers (92%). Multivariate analysis has revealed that the M/V784 polymorphism is a significant prognostic factor, being independent of the other conventional prognostic factors such as lymph node status and estrogen receptor status. CONCLUSION: These results suggest that the M/V784 polymorphism, but not the N/H372 polymorphism, would be useful in the selection of women at high risk for developing breast cancer and would also serve as a clinically useful prognostic factor in breast cancer patients.

Alleles↗