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PubMed2006

[Multicenter phase II trial of thrice-weekly docetaxel and weekly trastuzumab as preoperative chemotherapy in patients with HER 2-overexpressing breast cancer--Japan East Cancer Center Breast Cancer Consortium (JECBC) 02 Trial].

The efficacy and safety of combination therapy of 4 cycles with docetaxel 70 mg/m(2)every 3 weeks and trastuzumab as primary chemotherapy for operable breast cancer was determined in 21 patients (pts) by assessing the pathological complete response (pCR) rate, clinical response rate (RR), breast conservation surgery (BCS) rate and toxicities. To date, 19 pts have completed surgery. The pCR rate was 21% [95% CI 6%-46%] . The overall RR was 90% [95% CI 67%-99%] , with 5 CR, 12 PR, 2 SD and 0 PD. Grade 3 or 4 adverse events were leukopenia 48%, neutropenia 67%, hemoglobin 5%, and febrile neutropenia 10%. All non-hematological toxicities were mild and manageable. The pCR rate is not as low as that achieved in previous international studies. The combination of docetaxel and trastuzumab was a well-tolerated and very active regimen for the treatment of patients with HER 2-overexpressing operable breast cancer. This regimen promises to be one of the leading future treatments for progressive breast cancer.

Adult↗

PubMed1993

Topoisomerase II alpha co-amplification with erbB2 in human primary breast cancer and breast cancer cell lines: relationship to m-AMSA and mitoxantrone sensitivity.

Topoisomerase II alpha (topo II alpha) is a key enzyme in DNA replication and a target for many anti-cancer drugs. High levels are associated with sensitivity to topoisomerase II inhibitors. Because its chromosome location is similar to erbB2 (17q21-22), which is frequently amplified in breast cancer, co-amplification of these genes was assessed. In 117 primary breast cancers, 25 were amplified for erbB2. Three of these cases showed co-amplification of topo II alpha. Topo II beta was not amplified. Four human breast cancer cell lines were assessed for erbB2 and topo II alpha co-amplification. They were also analysed for sensitivity to the topoisomerase inhibitors m-AMSA and mitoxantrone. The most sensitive cell line was SKBr3, which was the only one with erbB2 amplification. Topo II alpha was co-amplified to a similar extent as in tumours. This suggests that patients whose tumours show topo II alpha amplification should be assessed specifically for therapy with topoisomerase inhibitors.

Adult↗

PubMed2002

Current surgical management of breast cancer.

Breast cancer surgery continues to become more conservative. Supporting this conservatism are (1) earlier diagnosis through mammographic screening, (2) an increasing role for diagnostic ultrasound and magnetic resonance imaging, (3) the further development of image-guided core-needle biopsy, and (4) the advent of sentinel lymph node biopsy as an alternative to conventional axillary dissection. For patients with duct carcinoma in situ, the addition of radiotherapy and tamoxifen to surgical excision reduces local recurrence but has not yet improved survival over the rate observed with excision alone. There may be low-risk subgroups of duct carcinoma in situ patients for whom conservative surgery alone is adequate treatment. For patients with invasive cancer, breast conservation remains underutilized. A small survival benefit from post-mastectomy adjuvant radiotherapy is offset by an increased incidence of cardiovascular mortality, a phenomenon which has not yet been demonstrated for radiotherapy following breast conservation. Sentinel lymph node biopsy represents a new standard of care for axillary lymph node staging in the large majority of breast cancer patients with high-risk duct carcinoma in situ and stage I-II invasive cancers. The procedure is feasible, accurate, and works best with a combination of blue dye and radioisotope mapping. After proper validation studies, patients with negative sentinel lymph nodes do not require axillary dissection. The prognostic significance of sentinel lymph node micrometastases identified by enhanced pathologic techniques remains a matter of debate. Prophylactic mastectomy reduces breast cancer incidence and mortality among those with a high-risk family history, and mutations of BRCA1-2, but has significant adverse psychosocial sequelae for a small and unpredictable fraction of patients and should not be undertaken lightly. Prophylactic oophorectomy should be offered to all women with BRCA1-2 mutations, especially those beyond the years of childbearing.

Breast Neoplasms↗

PubMed1992

Randomized trial of adjuvant tamoxifen in node negative postmenopausal breast cancer. Stockholm Breast Cancer Study Group.

The paper presents long-term results of a randomized trial of adjuvant tamoxifen (40 mg daily for 2 or 5 years) versus surgery alone including 1,347 postmenopausal patients with histologically negative axillary nodes and a tumour diameter less than or equal to 30 mm. Data on the estrogen receptor status of the primary tumour were available in 1,136 patients (84%). At a median follow-up of 7 years (range 1.7-13.0 years) there was a significant prolongation of the recurrence-free survival among those allocated to tamoxifen (p less than 0.01), significantly fewer deaths due to breast cancer (p = 0.02) and a trend towards improved overall survival (p = 0.11). The treatment benefit was restricted to patients with ER-positive tumours. There was no significant reduction of breast cancer recurrences in the tamoxifen group among patients whose tumours were classified as ER-negative. The results support and extend previous studies in showing a long-term benefit of tamoxifen in postmenopausal breast cancer patients with node-negative, estrogen receptor positive disease.

Breast Neoplasms↗

PubMed1994

Timing of surgery in relation to menstrual cycle does not predict the prognosis in primary breast cancer. Danish Breast Cancer Cooperative Group.

From 1977 to 1989 6488 patients under 50 years with primary breast cancer were registered in the nationwide Danish Breast Cancer Cooperative Group (DBCG). Among these, information on last menstrual period prior to surgery was available in 1635 cases which constitute the study group of the present analysis. The group was representative of all women operated upon during the period with regard to prognostic factors and survival. In the study group time of surgery in relation to last menstrual period was found to have no influence on 5 and 10 years survival.

Adult↗

PubMed1997

Validation of existing and development of new prognostic classification schemes in node negative breast cancer. German Breast Cancer Study Group.

Several prognostic classification schemes in node negative breast cancer are proposed, but only the Nottingham Prognostic Index (NPI) seems to be sufficiently validated. Validation, which is a prerequisite for a sensible assessment, is not published for two recent proposals according to Glick et al. [1] and Rubens [2]. The German Breast Cancer Study Group (GBSG) entered 662 eligible patients in a prospective observational study. 603 of them had complete data for seven 'standard' prognostic factors and median follow-up is about 5 years. As there is no accepted and informative measure of separation for classification schemes presently available, we propose a new one and use it additionally to the well known logrank-test and Kaplan-Meier estimates to investigate the predictive power of the three schemes. significant differences in survival and recurrence-free survival could be established for the NPI subgroups but not for others where even the ordering of the groups was different. With the Cox model and the classification and regression tree approach we develop two new proposals for the differentiation of subgroups of node negative patients. As in the NPI, tumor size and grade are the most important factors, but with a different weighting scheme. Young age (< or = 40 years) and very high estrogen receptor values (> 300 fmol) in a small subgroup of patients were associated with worse prognosis. The new proposals showed a better degree of separation, which demonstrates that an improvement seems possible using standard factors. Because the measures of separation give an overoptimistic impression for the new proposals, a validation with other studies is necessary before a general recommendation can be given.

Adult↗

PubMed1999

Modelling the effects of standard prognostic factors in node-positive breast cancer. German Breast Cancer Study Group (GBSG).

Prognostic models that predict the clinical course of a breast cancer patient are important in oncology. We propose an approach to constructing such models based on fractional polynomials in which useful transformations of the continuous factors are determined. The idea may be applied with all types of regression model, including Cox regression, the method of choice for survival-time data. We analyse a prospective study of node-positive breast cancer. Seven standard prognostic factors--age, menopausal status, tumour size, tumour grade, number of positive lymph nodes, progesterone and oestrogen receptor concentrations--were investigated in 686 patients, of whom 299 had an event for recurrence-free survival and 171 died. We determine a final model with transformations of prognostic factors and compare it with the more traditional approaches using categorized variables or assuming a straight line relationship. We conclude that analysis using fractional polynomials can extract important prognostic information which the traditional approaches may miss.

Breast Neoplasms↗

PubMed2000

Safety and efficacy results of a randomized trial comparing adjuvant toremifene and tamoxifen in postmenopausal patients with node-positive breast cancer. Finnish Breast Cancer Group.

PURPOSE: In this multicenter trial, toremifene 40 mg/d was compared with tamoxifen 20 mg/d, both given orally for 3 years to postmenopausal, axillary node-positive women after breast surgery. PATIENTS AND METHODS: The first 899 patients (toremifene, n = 459; tamoxifen, n = 440) of the total of 1,480 patients accrued to the trial were included in this scheduled safety analysis. The mean follow-up time was 3.4 years. RESULTS: The two treatment groups were well balanced with respect to patient and disease characteristics. The subjective side-effect profile was similar in both treatment groups. Slightly more vascular complications (deep vein thromboses, cerebrovascular events, and pulmonary embolisms) were seen among tamoxifen-treated patients (5.9%) as compared with toremifene-treated patients (3.5%) (P: =.11), whereas bone fractures (P: =.09) and vaginal leukorrhea (P: =.05) were more common in the toremifene group. The number of subsequent second cancers was similar. The breast cancer recurrence rate was 23.1% (n = 106) in the toremifene group and 26.1% (n = 115) in the tamoxifen group (P: =.31). When only patients with estrogen receptor (ER)-positive cancer were considered (n = 556), the risk for breast cancer recurrence was nonsignificantly lower among the toremifene-treated women, with a hazards ratio of 0.74 (90% confidence interval, 0.52 to 1.04; P: =.14). The mean time to breast cancer recurrence and overall survival were similar in both groups. CONCLUSION: The side-effect profile of toremifene resembles that of tamoxifen. The efficacy of toremifene seems to be no less than that of tamoxifen. The trend for fewer breast cancer recurrences in the ER-positive subgroup is encouraging, but a longer follow-up is needed to confirm this.

Antineoplastic Agents, Hormonal↗

PubMed1992

Chemotherapy with or without high-dose medroxyprogesterone acetate in oestrogen-receptor-negative advanced breast cancer. Norwegian Breast Cancer Group.

In a randomised study 142 patients with advanced oestrogen-receptor-negative breast cancer in the tumour tissue received chemotherapy alone or chemotherapy combined with high doses (1000 mg daily) of oral medroxyprogesterone acetate (HD-MPA). Of the 126 fully evaluable for response, the response rates were 46% for chemotherapy alone and 73% for chemotherapy with HD-MPA (P = 0.005). There was no significant difference with regard to duration of response. Of the 138 patients evaluable for survival and toxicity, survival was shorter in the combined treatment group; median survival of 9 versus 13 months (P less than 0.05). Considerable toxicity was seen from HD-MPA, especially weight gain and fluid retention. The present study provides evidence that in concordance with preclinical studies an interaction between chemotherapy and HD-MPA may exist in breast cancer normally resistant to hormone therapy. The side-effects from MPA were substantial, however, and the survival data are of great concern.

Antineoplastic Agents↗

PubMed1999

Role of immunohistochemical detection of lymph-node metastases in management of breast cancer. International Breast Cancer Study Group.

BACKGROUND: This study was designed to ascertain whether immunohistochemical methods could improve the detection of metastases in primary breast-cancer patients whose axillary lymph nodes were classified, by conventional methods, as disease free. METHODS: Ipsilateral lymph nodes (negative for metastases by routine histology) from 736 patients (participants in Trial V of the International [Ludwig] Breast Cancer Study) were examined by serial sectioning and staining with haematoxylin and eosin (two sections from each of six levels) and by immunohistochemistry of a single section (with two anticytokeratins AE-1 and CAM 5.2). After median follow-up of 12 years, disease-free and overall survival were estimated by Kaplan-Meier methods. FINDINGS: Occult nodal metastases were detected by serial sectioning and haematoxylin and eosin in 52 (7%) of 736 patients and by immunohistochemistry in 148 (20%). Only two (3%) of 64 invasive lobular or mixed invasive lobular and ductal cancers had node micrometastases, detected by haematoxylin and eosin, compared with 25 (39%) by immunohistochemistry. Occult metastases, detected by either method, were associated with significantly poor disease-free and overall survival in postmenopausal but not in premenopausal patients. Immunohistochemically detected occult lymph-node metastases remained an independent and highly significant predictor of recurrence even after control for tumour grade, tumour size, oestrogen-receptor status, vascular invasion, and treatment assignment (hazard ratio 1.79 [95% CI 1.17-2.74], p=0.007). INTERPRETATION: The immunohistochemical examination of ipsilateral axillary lymph nodes is a reliable, prognostically valuable, and simple method for the detection of occult nodal metastases. Immunohistochemistry is recommended as a standard method of node examination in postmenopausal patients.

Adult↗

PubMed2000

Quality-of-life scores predict outcome in metastatic but not early breast cancer. International Breast Cancer Study Group.

PURPOSE: We compared the prognostic value of quality-of-life (QL) scores in the adjuvant setting and after relapse in two randomized trials of the International Breast Cancer Study Group. PATIENTS AND METHODS: More than 2,000 premenopausal and postmenopausal patients with node-positive breast cancer who were participating in randomized trials that compared adjuvant therapies completed QL assessments for physical well-being, mood, appetite, and coping at study entry and at months 3 and 18 if they remained relapse-free and, in case of relapse, at 1 month and at 6 months after relapse. Cox regression models were used to test the relationship between QL scores and disease-free survival (DFS), in the adjuvant setting, or overall survival, in the case of postrelapse QL measurement. All models were stratified by language/country group and included other factors related to QL and/or outcome. RESULTS: DFS was not significantly predicted by QL scores at baseline or month 18, or by changes in QL score between baseline and months 3 or 18. In contrast, after relapse, QL scores were predictive for subsequent overall survival. One month after relapse, better mood (P =.04) in premenopausal patients and better appetite (P =.005) in postmenopausal patients were associated with longer survival. Six months after relapse, better physical well-being (P =.03) and appetite (P =.03) in premenopausal patients and better physical well-being (P <.0001), mood (P =.002), appetite (P =.0001), and coping (P =.0001) in postmenopausal patients predicted longer survival. CONCLUSION: Any prognostic significance of QL scores in the adjuvant setting is minimal or obscured by chemotherapy effects, but there is strong prognostic significance of QL scores after disease relapse. The contrast suggests that patient perception of the severity of underlying illness may determine reported QL scores.

Breast Neoplasms↗

PubMed1992

Genetic predisposition to breast cancer.

Breast cancer is the most common cancer among American women. Because metastatic breast cancer is an incurable disease, efforts to decrease breast cancer mortality have focused on early detection and improved treatment. Identification and analysis of a specific genetic susceptibility could permit detection of susceptible women and greatly increase the understanding of the initial step that eventually leads to cancer. Because susceptibility loci have been recognized as sites that often are altered during tumor progression, the identification and cloning of such loci could be important in developing cancer therapies. In this article, the progress being made in segregation analysis, linkage analysis, and cloning of breast cancer susceptibility loci is reviewed. The evidence for genetic inheritance is most consistent with dominant inheritance for at least three major susceptibility loci. Proliferative breast disease has been hypothesized to be an inherited lesion in breast cancer kindreds with both premenopausal and postmenopausal probands. Currently, there are many genetic markers for mapping the human genome. Technologic advances have progressed from restriction fragment length polymorphisms to highly polymorphic markers. Using this technology, breast cancer susceptibility in some kindreds with an early onset has been shown to be linked to chromosome 17q. Gene isolation eventually will follow with an increased understanding of the percentage of breast cancer cases that are a result of this genetic locus. Li-Fraumeni syndrome, which often is expressed as breast cancer, is due to mutations in the p53 gene. Characterization of the syndrome and its relationship to the altered gene should proceed rapidly. There is also a group of families exhibiting a genetic susceptibility that is not due to either of these loci. Together, these findings indicate that there are at least three separate major loci segregating for breast cancer susceptibility. With the current initiative to map and sequence the entire human genome and the advances that recently have been reported, a detailed molecular understanding of breast cancer predisposition can be envisaged.

Age Factors↗

PubMed2006

Interrelationships between cyclooxygenases and aromatase: unraveling the relevance of cyclooxygenase inhibitors in breast cancer.

Breast cancer is the most common cancer among women, and ranks second among cancer deaths in women. Approximately 60% of all breast cancer patients have hormone-dependent breast cancer, which contains estrogen receptors and requires estrogen for tumor growth. Estradiol is biosynthesized from androgens by the cytochrome P450 enzyme complex called aromatase. Aromatase is found in several tissues in the body and aromatase (CYP19) gene expression is regulated in a tissue-specific manner via use of alternative promoters. Aromatase transcript expression and activity in breast tumor tissue is greater than that in the normal breast tissue, and prostaglandins can increase CYP19 expression and aromatase activity in breast cancer cells. Cyclooxygenase (COX) is a key enzyme in the production of prostaglandins. Studies have shown higher levels of COX-2 isoform in breast cancer tissue when compared to normal breast tissue, and this is accompanied by high concentrations of prostaglandin E(2) (PGE(2)). Previous studies suggest a strong association between CYP19 gene expression and the expression of COX genes. While studies have shown that nonsteroidal anti-inflammatory drugs (NSAIDs) have beneficial effects on breast cancer, the mechanism by which this occurs is still unclear. Studies have shown that COX inhibitors decrease aromatase activity in breast cancer cells and this effect starts at the transcriptional level. Real time PCR data shows that this molecular mechanism involves promoters I.4 and II, the promoters involved in the development of breast cancer. High levels of COX-2 expression result in higher levels of prostaglandin E(2) (PGE(2)), which in turn increases CYP19 expression through increases in intracellular cyclic AMP levels and activation of promoter II. Thus, PGE(2) produced via COX may act locally in paracrine and autocrine fashion to increase the biosynthesis of estrogen by aromatase in hormone-dependent breast cancer development.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMedDate not supplied

Trastuzumab: targeted therapy for the management of HER-2/neu-overexpressing metastatic breast cancer.

Breast cancers are a biologically heterogeneous group of mammary tumors with distinct natural histories and varied responses to established therapies. They have long been divided into those that are hormone sensitive [as defined by expression of the estrogen receptor alpha (ERalpha) and/or the progesterone receptor (PR)] and those that are not. Notably, only those breast cancers that express ERalpha and/or PR typically respond to hormonal therapy with tamoxifen, aromatase inhibitors, or the newer agent fulvestrant. More recently, the transmembrane tyrosine kinase receptor HER-2/neu was identified as an oncogene overexpressed by about 30% of breast cancers. These HER-2/neu-overexpressing breast cancers define a subset of breast tumors that are characteristically more aggressive, and women who develop them have a shorter survival. Trastuzumab (Herceptin), a humanized monoclonal antibody specific for HER-2/neu, has revolutionized the management of metastatic HER-2/neu-overexpressing breast cancers. As a single agent, it produces response rates similar to those of many single-agent chemotherapeutic agents active in metastatic breast cancer and has limited toxicity. Combining trastuzumab with chemotherapy can result in synergistic antitumor activity. The clear efficacy of trastuzumab against HER-2/neu-overexpressing metastatic breast cancer has led to a keen interest in testing its role in the management of early breast cancer, and multiple large clinical trials are currently in progress. This review summarizes the available clinical data on the use of trastuzumab in HER-neu-overexpressing breast cancer and briefly highlights emerging opportunities for innovative, trastuzumab-based breast cancer therapies.

Animals↗

PubMed1997

Pathology of familial breast cancer: differences between breast cancers in carriers of BRCA1 or BRCA2 mutations and sporadic cases. Breast Cancer Linkage Consortium.

BACKGROUND: A few breast cancer cases are attributable to a hereditary predisposition to the disease. We aimed to compare the histological features of breast cancer in women carrying mutations in the susceptibility genes BRCA1 and BRCA2 with controls unselected for family history. METHODS: The morphological characteristics of specimens from 440 patients with familial breast cancer, including 118 in carriers of BRCA1 mutations and 78 in carriers of BRCA2 mutations, were compared with those from 547 age-matched controls, unselected for family history, by seven pathologists. FINDINGS: Cancers in carriers of BRCA1 (p < 0.0001) and BRCA2 mutations (p = 0.04) were, on average, of a higher overall grade than in controls. For example, the proportions in grade 3 were 66% of 139, 41% of 58 and 36% of 368 specimens, respectively. However, when the three grade indices were considered independently, breast cancers in BRCA1-mutation carriers showed more pleomorphism (p = 0.006), a higher mitotic count (p < 0.0001), and less tubule formation than controls (p = 0.006), whereas cancers in BRCA2-mutation carriers showed less tubule formation (p = 0.003), but no difference in pleomorphism or mitotic count. The occurrence of invasive lobular carcinoma and invasive ductal carcinoma was not significantly different between carriers of BRCA1 or BRCA2 mutations and controls. Medullary or atypical medullary carcinoma was, however, found more often in BRCA1 (13%, p < 0.0001) than in BRCA2-mutation carriers (3%) or controls (2%). Tubular carcinoma was less common in BRCA2-mutation carriers. The few mucoid carcinomas were all in familial cases. Carriers of BRCA1 mutations showed less ductal carcinoma in situ around the invasive lesion than controls (41 vs 56%, p = 0.001). Lobular carcinoma in situ was less common in familial cancers (p = 0.013), but differences were not significant for BRCA1-mutations or BRCA2-mutation carriers, separately. INTERPRETATION: The histology of breast cancers in predisposed women differs from that in sporadic cases, and there are differences between breast cancers in carriers of BRCA1 and BRCA2 mutations. The findings suggest that breast cancer due to BRCA1, has a different natural history to BRCA2 or apparently sporadic disease, which may have implications for screening and management.

Adenocarcinoma↗

PubMed2005

Epidemiology of male breast cancer.

Breast cancer in men is a rare disease, accounting for approximately 1% of all breast cancer cases. Although the epidemiologic literature regarding female breast cancer is extensive, relatively little is known about the etiology of male breast cancer (MBC). This review is intended to summarize the existing body of evidence on genetic and epidemiologic risk factors for breast cancer in men. Overall, the epidemiology of MBC presents similarities with the epidemiology of female breast cancer. Major genetic factors associated with an increased risk of breast cancer for men include BRCA2 mutations, which are believed to account for the majority of inherited breast cancer in men, Klinefelter syndrome, and a positive family history. Suspected genetic factors include AR gene mutations, CYP17 polymorphism, Cowden syndrome, and CHEK2. Epidemiologic risk factors for MBC include disorders relating to hormonal imbalances, such as obesity, testicular disorders (e.g., cryptorchidism, mumps orchitis, and orchiectomy), and radiation exposure. Suspected epidemiologic risk factors include prostate cancer,prostate cancer treatment, gynecomastia, occupational exposures (e.g., electromagnetic fields, polycyclic aromatic hydrocarbons, and high temperatures), dietary factors (e.g., meat intake and fruit and vegetable consumption), and alcohol intake.

Biomarkers, Tumor↗

PubMed1993

[Combination therapy with low dose adriamycin for advanced or recurrent breast cancer. Hokkaido Breast Cancer Treatment Study Group].

Comparative clinical trials among 3 regimens for patients with advanced or recurrent breast cancer were performed as a multi-institutional joint study. Arm-I of 3 regimens consisted of a 3-day consecutive administration of adriamycin (ADM) at 10 mg/body every 4 weeks, a daily oral administration of cyclophosphamide (CPA), 5-FU and tamoxifen (TAM) at 100 mg, 200 mg, and 20 mg, respectively, and a once-a-week intramuscular or subcutaneous injection of OK-432 (OK) gradually increased from the initial dose of 1 KE to the maintenance dose of 5 KE. Arm-II contained methotrexate (MTX) at 10 mg/body for 3 consecutive days every 4 weeks in place of ADM in Arm-I. Arm-III contained neither ADM nor MTX. Of 69 cases registered, 52 were eligible, leaving 6 non-eligible and 11 incomplete cases. The results of the overall evaluation of 48 complete cases other than 4, in which the tumor was not exactly measured, were as follows. Arm-I resulted in 2 CR and 3 PR out of 19 cases, the response rate being 23.6% (5/19). Arm-II resulted in 1 CR out of 15, the response rate being 6.7% (1/15). In Arm-III, no response cases were found. No significant difference was observed among three treatment groups (p = 0.055), but in Arm-I, the response rate was higher than in the other treatment groups, suggesting that there is a probability of useful combined use of ADM.

Adult↗

PubMed1986

[Heterogeneity of breast cancer].

Breast cancer is in many aspects a heterogeneous disease. This becomes also evident in family studies. The families of 116 women with breast cancer with 50 years and less at diagnosis were compared to than of 161 breast cancer patients with 51 years and more with respect to breast cancer in the relatives. Younger breast cancer patients had more second degree relatives with breast cancer. Probands with a positive family history were on the average 10 years younger than probands with a negative family history. A positive family history increases breast cancer risk by 4.3 times for first degree relatives and by 2.3 times for second degree relatives in comparison to the general population. These results point to an etiological heterogeneity of breast cancer.

Adult↗