Pure antiestrogens. The most important advance in the endocrine therapy of breast cancer since 1896.
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Antineoplastic Agents, Hormonal↗
Biomedical subjects
C K Osborne
Publications and source records attributed to C K Osborne.
Adjuvant chemotherapy plus tamoxifen compared with tamoxifen alone for postmenopausal breast cancer: meta-analysis of quality-adjusted survival.
BACKGROUND: Adjuvant tamoxifen for early breast cancer provides an improvement in relapse-free (RFS) and overall survival (OS), especially for older women. We carried out a meta-analysis to find out whether the benefit of adding chemotherapy to tamoxifen outweighs its costs in terms of toxic effects for postmenopausal patients. METHODS: The meta-analysis of quality-adjusted survival was based on data from 3920 patients aged 50 years or older with node-positive breast cancer randomly assigned in nine trials that compared combination chemotherapy plus tamoxifen with tamoxifen alone. The nine trials were included in the worldwide overview conducted by the early breast cancer trialists' collaborative group (EBCTCG). The quality-adjusted time without symptoms or toxicity (Q-TWiST) method was used to provide treatment comparisons incorporating differences in quality of life associated with subjective toxic effects of treatment and symptoms of disease relapse. FINDINGS: Within 7 years of follow-up the modest benefit of increased RFS and OS for patients who received chemotherapy just balanced the costs in terms of acute toxic side-effects. Chemotherapy-treated patients gained an average of 5.4 months of RFS and 2 months of OS (neither statistically significant), but had to receive cytotoxic treatment for between 2 and 24 months to achieve these gains. No values of preference weights for time spent undergoing chemotherapy and time after relapse gave significantly more Q-TWiST with chemotherapy plus tamoxifen than with tamoxifen alone. INTERPRETATION: Within 7 years of follow-up, adjuvant chemoendocrine therapy did not provide more quality-adjusted survival time than tamoxifen alone for women aged 50 years or older with node-positive breast cancer. Better selection and administration of chemotherapy regimen, different scheduling of chemotherapy and tamoxifen, and appropriate use of patient and tumour characteristics may increase the therapeutic advantage of the combination.
Antineoplastic Agents, Hormonal↗
Adjuvant CMFVP versus adjuvant CMFVP plus ovariectomy for premenopausal, node-positive, and estrogen receptor-positive breast cancer patients: a Southwest Oncology Group study.
PURPOSE: To determine whether the addition of surgical ovariectomy to standard chemotherapy prolongs disease-free survival (DFS) and overall survival in premenopausal patients with estrogen receptor (ER)-positive operable breast cancer with positive axillary nodes. PATIENTS AND METHODS: Three hundred fourteen premenopausal patients with ER-positive, node-positive breast cancer were enrolled between July 1979 and July 1989. Patients were stratified according to number of involved nodes and type of primary surgery and randomized to receive either of the following: (1) cyclophosphamide 60 mg/m2/d by mouth for 1 year, methotrexate 15 mg/m2 intravenously (i.v.) weekly for 1 year, fluorouracil (5-FU) 400 mg/m2 i.v. weekly for 1 year, vincristine .625 mg/m2 i.v. weekly for the first 10 weeks, and prednisone weeks 1 to 10 with doses decreasing from 30 mg/m2 to 2.5 mg/m2 (CMFVP); or (2) bilateral ovariectomy followed by CMFVP. RESULTS: The median follow-up time is 7.7 years and the maximum 13.2 years. Treatment arms are not significantly different with respect to either survival or DFS (one-sided log-rank, P = .55 and .70, respectively). The 7-year survival rate is 71% on the CMFVP arm and 73% on CMFVP plus ovariectomy. No significant differences were observed in node or receptor level subsets. CONCLUSION: We conclude that, in this study, the addition of ovariectomy did not improve results over chemotherapy alone in the treatment of premenopausal women with node-positive, ER-positive, operable breast cancer. Our sample size was too small to detect a small improvement. The death hazards ratio of CMFVP/CMFVP plus ovariectomy was 1.22 (95% confidence interval [CI], .79 to 1.89).
Antineoplastic Combined Chemotherapy Protocols↗
Influence of patient characteristics, socioeconomic factors, geography, and systemic risk on the use of breast-sparing treatment in women enrolled in adjuvant breast cancer studies: an analysis of two intergroup trials.
PURPOSE: To investigate the frequency of breast-sparing treatment among breast cancer patients subsequently enrolled in national cooperative group studies of adjuvant chemotherapy. PATIENTS AND METHODS: A data base was formed of 5,172 patients randomized onto two intergroup trials. Lumpectomy rates were analyzed within study-defined risk strata and across geographic regions. Significant predictors of lower lumpectomy usage were determined in multivariate analyses with variables that described patient and disease characteristics, systemic risk strata, geographic region, and socioeconomic indicators based on zip code of residence. RESULTS: Breast-conservation rates were 30% in the node-negative and 15% in the node-positive trials, with a wide geographic variation within each study (range, 14% to 49% and 9% to 31%, respectively). Lumpectomy use declined with increasing tumor size and did not exceed 40% even for tumors < or = 1 cm with negative nodes. With increasing risk of systemic relapse, frequency of lumpectomy declined (rates for five strata in order of increasing systemic risk: 41%, 33%, 24%, 18%, and 11%), even though these strata were not known at the time of the surgical decision. A logistic model confirmed the joint significance of geographic region and systemic risk. An exploratory model that adjusted for all important variables identified the following significant predictors of lower lumpectomy use: positive nodes; many positive nodes, increased systemic risk; tumor size > or = 2.0 cm; older age; South, Central or non-New England regions; and either lack of college degree or lower income levels. CONCLUSION: Breast-sparing therapy was used in the minority of women subsequently accrued to two national adjuvant breast cancer studies, even though this cohort and their referring surgeons represented a select population. Although multiple concrete factors were independent predictors of lower lumpectomy rates, prospective research is needed into how patients and their physicians approach the mastectomy versus lumpectomy decision.
Adult↗
Aromatase inhibitors in the treatment of advanced breast cancer. Introduction.
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Antineoplastic Agents, Hormonal↗
Prognostic value of Ki-67 compared to S-phase fraction in axillary node-negative breast cancer.
The primary purpose of this study was to evaluate the prognostic significance of Ki-67, a cell proliferation-associated antigen, in a large group (n = 674) of axillary node-negative breast cancer cases with long-term follow-up and to correlate Ki-67 antigen expression with S-phase fraction. Ki-67 immunostaining was assessed both semiquantitatively and quantitatively. The statistical analysis focused on agreement between methods of Ki-67 quantification, agreement between Ki-67 and S-phase fraction, associations between Ki-67 and other clinical variables, and prognostic value of Ki-67. There was excellent agreement between the two methods of Ki-67 assessment (Spearman rank correlation, rsp = 0.91; P = 0.0001; n = 674) but only weak correlation between either semiquantitative or quantitative Ki-67 and S-phase fraction (rsp = 0.12 and rsp = 0.15, respectively). Ki-67 (overall median, 2%) was independent of tumor size and modestly related to other measures of tumor aggressiveness. Using a cutpoint of 5% (percentage of tumor cells), cases with high Ki-67 exhibited a significantly shorter disease-free survival (Padj = 0.004). In multivariate analysis, high Ki-67 was associated with a 1.8-fold increased risk of recurrence (P = 0.001). In the subgroup with S-phase data, the adjusted relative risk (hazard ratio, 1.9; P = 0.02) was unchanged by inclusion of S phase in the model. This suggests that Ki-67 provides significant independent prognostic information in addition to that contained in tumor size and S-phase fraction.
Breast Neoplasms↗
The small heat shock protein HSP27 is not an independent prognostic marker in axillary lymph node-negative breast cancer patients.
Heat shock protein 27 (hsp27) belongs to the family of heat shock proteins and is thought to be involved in thermotolerance, cell proliferation, drug resistance, and chaperone processes. The aim of this study was to investigate whether hsp27 levels are correlated with clinical outcome in axillary lymph node-negative breast cancer patients. We describe a Western blot study measuring hsp27 levels in 425 patients and an immunohistochemistry (IHC) study analyzing 788 patients. Results obtained by both methods were concordant. Univariate survival analysis was performed considering hsp27 either as an optimally dichotomized variable or as a continuous variable. Additional data include age at biopsy, tumor size, estrogen receptor (ER) and progesterone receptor status, tumor ploidy and percentage of cells in S phase, and adjuvant therapy. hsp27 levels correlated positively with ER status (P = 0.0001 in Western blot and IHC study), progesterone receptor status (P = 0.0001 in Western blot and IHC study), and aneuploidy (Western blot study, P = 0.0012; IHC study, P = 0.0004) but not with tumor size (Western blot study, P = 0.69; IHC, P = 0.53) or S phase (Western blot study, P = 0.19; IHC study, P = 0.38). Overall, there was no relationship between hsp27 expression and disease-free survival (Western blot study, P = 0.70/0.54; IHC, P = 0.47/0.30) or overall survival (Western blot study, P = 0.16/0.15; IHC, P = 0.46/0.78). Exploratory subset analyses defined by ER status and use of adjuvant treatment indicated that in ER+/untreated patients, high hsp27 levels correlated modestly with shorter disease-free survival (Western blot, P = 0.04/0.04; IHC, P = 0.11/0. 03). hsp27 is not a useful prognostic marker for the clinic in axillary lymph node-negative patients. However, the finding of modest prognostic value of hsp27 in the subgroup of ER+/untreated patients raises new questions about the biological function of hsp27 in breast cancer.
Adult↗
Aberrant subcellular localization of BRCA1 in breast cancer.
The BRCA1 gene product was identified as a 220-kilodalton nuclear phosphoprotein in normal cells, including breast ductal epithelial cells, and in 18 of 20 tumor cell lines derived from tissues other than breast and ovary. In 16 of 17 breast and ovarian cancer lines and 17 of 17 samples of cells obtained from malignant effusions, however, BRCA1 localized mainly in cytoplasm. Absence of BRCA1 or aberrant subcellular location was also observed to a variable extent in histological sections of many breast cancer biopsies. These findings suggest that BRCA1 abnormalities may be involved in the pathogenesis of many breast cancers, sporadic as well as familial.
Amino Acid Sequence↗
Accumulation of p53 protein as a possible predictor of response to adjuvant combination chemotherapy with cyclophosphamide, methotrexate, fluorouracil, and prednisone for breast cancer.
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Antineoplastic Combined Chemotherapy Protocols↗
Comparison of the effects of a pure steroidal antiestrogen with those of tamoxifen in a model of human breast cancer.
BACKGROUND: Tamoxifen, a nonsteroidal estrogen antagonist, is the most prescribed drug for the treatment of breast cancer. The use of tamoxifen is limited, however, by the development of resistance to this compound in most patients. Although tamoxifen behaves primarily as an estrogen antagonist, it has agonist (or growth-stimulatory) activity as well. ICI 182,780 is a 7 alpha-alkylsulfinyl analogue of estradiol lacking agonist activity. The absence of agonist activity may make this steroidal antiestrogen superior to tamoxifen in suppressing tumor cell growth. PURPOSE: We compared the inhibitory effects of ICI 182,780, tamoxifen, and estrogen withdrawal on the growth of established tumors and on tumorigenesis in a model system that uses estrogen-dependent, human MCF-7 breast tumor cells growing in athymic nude mice. We also studied the hormonal responsiveness of tumors that became resistant to the two estrogen antagonists and the effects of these drugs on estrogen-regulated gene expression. METHODS: MCF-7 cells were injected subcutaneously into the flanks of castrated, female nude mice. The effects of repeated doses of tamoxifen and ICI 182,780 (500 micrograms and 5 mg, respectively) on the growth of established tumors (8-10 mm in size) were determined after supplemental estrogen was removed. The effects of antiestrogen treatments on the process of tumorigenesis, in the absence of estrogen supplementation, were determined by initiating drug administration on the same day as tumor cell inoculation. To evaluate the hormonal responsiveness of tumors resistant to tamoxifen and ICI 182,780, 1-mm3 segments of the tumors were transplanted onto the flanks of new recipient mice, which were then treated with estrogen or the antiestrogens--alone or in combination. Tumor growth was monitored by measuring tumor volumes twice a week. Expression of the estrogen-responsive genes, pLIV1 and pS2, in the tumors of treated animals was analyzed using blots of total cellular RNA and complementary DNA probes. RESULTS: Treatment with ICI 182,780 suppressed the growth of established tumors twice as long as treatment with tamoxifen or estrogen withdrawal. Tumorigenesis, in the absence of supplemental estrogen, was delayed to a greater extent in ICI 182,780-treated mice than in tamoxifen-treated mice. ICI 182,780 was found to be more effective than tamoxifen in reducing the expression of estrogen-regulated genes. Most tumors eventually became resistant to ICI 182,780 and grew independently of estrogen. CONCLUSIONS: ICI 182,780 is a more effective estrogen antagonist than tamoxifen in the MCF-7 tumor cell/nude mouse model system.
Analysis of Variance↗
Urokinase receptor in breast cancer tissue extracts. Enzyme-linked immunosorbent assay with a combination of mono- and polyclonal antibodies.
Urokinase plasminogen activator (uPA) is a proteolytic enzyme involved in degradation of the extracellular matrix during cancer invasion. The levels of uPA and its inhibitor PAI-1 in tumor extracts have previously been demonstrated to be of prognostic value in breast cancer as well as other types of cancer. We have previously characterized a specific cell surface receptor for uPA (uPAR) which strongly enhances the catalytic activity of uPA and is expressed during mammary cancer invasion. In order to quantitate uPAR in breast cancer tissue, we have now developed a sensitive enzyme-linked immunosorbent assay (ELISA), with polyclonal catching antibodies and three monoclonal detecting antibodies. The detection limit of the assay is approximately 0.16 fmol of uPAR in a volume of 100 microliters (1.6 pM). There is a linear relationship between signal and uPAR concentration up to at least 6.6 fmol per 100 microliters (66 pM). Both free uPAR and uPAR in complex with uPA is detected. The recovery of an internal uPAR standard in breast cancer tissue extracts is above 87%. The intra-assay and inter-assay variation coefficients are 7% and 13%. In order to find a suitable buffer for extraction of various components of the uPA-system from breast cancer tissue, we tested buffers which previously have been used for optimal extraction of estrogen receptor (A), uPA (B), and uPAR (C). Buffer A and B extracted approximately 30% and 50%, respectively, of the amount of uPAR extracted with buffer C.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Genetic aberrations detected by comparative genomic hybridization predict outcome in node-negative breast cancer.
Breast cancer progression is determined by a complex pattern of multiple genetic aberrations the association of which with patient prognosis is unknown. In this study, we have undertaken a genome-wide screening to detect genetic changes associated with clinical outcome in node-negative breast cancer. Comparative genomic hybridization was used to screen for DNA sequence gains and losses across all human chromosomes in 23 tumors from node-negative breast cancer patients with no disease recurrence after at least 5 years of follow-up and in 25 node-negative patients with recurrence during the first 5 years of follow-up. The total number of genetic aberrations (copy number gains and losses) per tumor was significantly greater in the recurrence group (P = 0.019) and in the subgroup of these patients who died as a result of breast cancer (P = 0.0022). When copy number losses and gains were analyzed separately, only losses were significant (P = 0.013 for recurrence and P = 0.002 for overall survival). Of the individual loci involved, a high level gain of the long arm of chromosome 8 was significantly associated with recurrence (P = 0.01, Fisher's exact test). Furthermore, amplification of DNA sequences at chromosome 20q12-13 was found in 7 cases (15%), 6 of which had early recurrence within 32 months of diagnosis. This genome-wide overview by comparative genomic hybridization suggests that genetically advanced node-negative breast cancers having a high overall number of genetic aberrations may have a poor prognosis and that increased copy number of two specific regions, 8q and 20q13, may confer a more aggressive phenotype. Results of this pilot study suggest that determination of the total number of DNA sequence copy number aberrations may help therapeutic decision making. Specific probes should be developed to test the prognostic value of 8q and 20q12-13 amplifications in large numbers of patients.
Aged↗
Tumor receptor imaging: proceedings of the National Cancer Institute workshop, review of current work, and prospective for further investigations.
In February 1994, the National Cancer Institute held a workshop to evaluate the current and future role of emission tomographic imaging methods, positron emission tomography and single-photon emission computed tomography, in improving the accuracy of cancer diagnosis and the effectiveness of treatment and in elucidating basic aspects of human cancer biology. Reviews covered many of the receptor and transport systems for hormones and growth factors, as well as metabolic changes important in human cancer, and topical presentations reviewed the current status of receptor-based imaging in the most well-characterized systems: somatostatin receptor imaging of neuroendocrine tumors, estrogen receptor imaging of breast cancer, and epidermal growth factor receptor and tumor metabolic imaging. A critical analysis was made of the current research and of new directions for the future development and use of receptor-imaging methods in oncology. In each area, recommendations were made for further investigation, where emerging understanding of tumor cell biology and defined molecular targets might be combined with the methods of radiopharmaceutical design and evaluation, to develop new approaches to critical issues in the diagnosis, staging, and treatment of cancer through tumor receptor imaging.
Humans↗
Recruitment with high physiological doses of estradiol preceding chemotherapy: flow cytometric and therapeutic results in women with locally advanced breast cancers--a Southwest Oncology Group study.
One theoretical method of increasing chemotherapeutic efficacy in breast cancer is to temporarily increase the number of tumor cells in cycle through hormonal recruitment prior to initiation of chemotherapy. In an effort to determine when and if this could be reliably accomplished, 50 women with locally advanced and/or metastatic breast cancer with known estrogen receptor (ER) status were entered into a serial breast biopsy study designed to measure increases in S-phase fraction (SPF) and proliferative index (PI; S + G2 + M) following administration of a high physiological dose of estrogen via estradiol vaginal suppositories prior to chemotherapy. Blood levels of estradiol were maintained in a range (0.5-5 nM) known to increase SPF in vitro. Compliance with suppository administration was monitored by serial blood sampling. Tumors were sampled at 0, 24, 48, 72, and/or 96 h. Thirty-one ER-positive and 9 ER-negative women had evaluable baseline biopsies and at least 1 subsequent biopsy. An increase was seen for SPF in 20 (69%) and for PI in 23 (79%) of 29 ER-positive patients at 48 h after estrogen initiation (95% confidence intervals, 49-85% for SPF and 60-92% for PI); similar increases were seen at 72 h. Median baseline SPF and PI values in ER-positive patients for whom increases were noted at 48 h were 6.2 and 8.5%, respectively. The median relative increases in these patients were 170 and 100%, respectively, at 48 h. The increases observed at 24 h in 4 (SPF) and 6 (PI) of the 9 ER-negative patients could have occurred by chance alone. Twenty-five of the 28 locally advanced (T4 and/or N2-3) patients achieved a complete response during combined modality treatment (estradiol-chemotherapy, mastectomy, and radiation). At a minimum follow-up time of 42 months, estimated 5-year progression-free and overall survivals are 30 and 49%, respectively, with a median time to progression of 35 months. Twenty-two women had metastatic disease (19 also had locally advanced disease). Thirteen had a complete or partial response, with a median duration of 12 months. Median progression-free and over-all survival times for all metastatic patients are 4 and 17 months, respectively. Estimated 5-year survival for metastatic disease patients is 27%. A high physiological dose of estrogen administered to patients with locally advanced ER-positive tumors can reliably increase the tumor SPF and PI within 48 h.(ABSTRACT TRUNCATED AT 400 WORDS)
Breast Neoplasms↗
Current trials and future directions of the Southwest Oncology Group Breast Cancer Committee.
The first adjuvant breast cancer trial in the Southwest Oncology Group (SWOG) was initiated in 1974. The trial eventually demonstrated that combination chemotherapy with cyclophosphamide, methotrexate, 5-fluorouracil, vincristine, and prednisone was superior to single-agent chemotherapy with melphalan in premenopausal and postmenopausal patients. Subsequently, SWOG has performed a series of adjuvant chemotherapy trials either alone or in collaboration with other cooperative groups. Over the past 5 years, SWOG has accrued more than 8000 patients to different clinical trials in primary and advanced breast cancer as well as to a series of ancillary biologic studies primarily evaluating new prognostic factors, such as hormone receptor status and flow cytometry. Current questions being addressed by SWOG breast cancer adjuvant trials include the value of doxorubicin in lymph node-negative patients, of chemoendocrine therapy in lymph node-positive premenopausal and post-menopausal patients, and of high dose chemotherapy with autologous bone marrow transplantation in high risk lymph node-positive patients. Trials in patients with metastatic disease are evaluating medical castration with the luteinizing hormone-releasing hormone agonist Zoladex (Zeneca Pharmaceuticals, Wilmington, DE), high dose chemotherapy and bone marrow transplantation, and newer agents such as paclitaxel (Taxol, Bristol-Myers Squibb, Walingford, CT). Future adjuvant trials will compare optimal sequential use of single-agent chemotherapy versus more traditional combination chemotherapy and address questions of dose intensity and the value of the addition of Taxol in the adjuvant setting. A trial using the synthetic retinoid 4-hydroxyphenylretinamide is also in the planning stage.
Antineoplastic Combined Chemotherapy Protocols↗
Tumor biologic factors and breast cancer prognosis among white, Hispanic, and black women in the United States.
BACKGROUND: In the United States, prognosis and survival after the diagnosis of breast cancer is poorer among black patients and, to a lesser extent, among Hispanic patients, compared with white patients. Patients who are black or Hispanic have been reported to present with higher stage or more advanced disease. Even after adjusting for stage, however, survival rates are lower for blacks but not for Hispanics. PURPOSE: Our purpose was to compare survival, age, tumor size, nodal status, estrogen-receptor (ER) and progesterone-receptor (PgR) status, histologic type, S-phase fraction, DNA ploidy status, HER-2/neu protein expression, and p53 protein status, along with systemic treatment, in a large group of white, black, and Hispanic U.S. women. METHODS: From 1970 to 1991, breast tumor specimens were submitted to The University of Texas Health Science Center from 31 contributing hospitals throughout the United States for ER and PgR assay. A total of 4885 white, 1016 black, and 777 Hispanic women were eligible for this study. Median follow-up was 57 months. RESULTS: Overall, white women were significantly more likely to be older and to have smaller tumors, have less lymph node involvement, have tumors with positive ER and PgR status, and have a lower S-phase fraction compared with Hispanic or black women. There were no clinically important differences in DNA ploidy, histologic type, HER-2/neu, and p53 expression among the three groups. Considering all stages, white women had the best overall survival (date of diagnosis to date of death) at 5 years--75% +/- 1% (means +/- SE), with a median survival of 166 months, but Hispanic women had an intermediate survival--70% +/- 2% (median survival, 156 months), and black women had the worst survival--65% +/- 2% (median survival, 117 months) (P < .0001). For node-negative patients, there was no significant difference in disease-free survival (date of diagnosis to date of first recurrence) or overall survival, although blacks tended to have a worse prognosis. For node-positive or locally advanced disease and for metastatic disease, blacks had significantly (P < .0001) worse disease-free and overall survival than did white or Hispanic women. Differences in the use of systemic therapy did not explain these outcomes. CONCLUSION: A number of biologic factors associated with poor prognosis are found with a significantly increased frequency in breast tumors from Hispanic and, particularly, from black women. Tumors with a more aggressive biology could lead to a higher stage at diagnosis and a poorer survival for the group as a whole.
Adult↗
The SH2 domain protein GRB-7 is co-amplified, overexpressed and in a tight complex with HER2 in breast cancer.
SH2 domain proteins are important components of the signal transduction pathways activated by growth factor receptor tyrosine kinases. We have been cloning SH2 domain proteins by bacterial expression cloning using the tyrosine phosphorylated C-terminus of the epidermal growth factor receptor as a probe. One of these newly cloned SH2 domain proteins, GRB-7, was mapped on mouse chromosome 11 to a region which also contains the tyrosine kinase receptor, HER2/erbB-2. The analogous chromosomal locus in man is often amplified in human breast cancer leading to overexpression of HER2. We find that GRB-7 is amplified in concert with HER2 in several breast cancer cell lines and that GRB-7 is overexpressed in both cell lines and breast tumors. GRB-7, through its SH2 domain, binds tightly to HER2 such that a large fraction of the tyrosine phosphorylated HER2 in SKBR-3 cells is bound to GRB-7. GRB-7 can also bind tyrosine phosphorylated SHC, albeit at a lower affinity than GRB2 binds SHC. We also find that GRB-7 has a strong similarity over > 300 amino acids to a newly identified gene in Caenorhabditis elegans. This region of similarity, which lies outside the SH2 domain, also contains a pleckstrin homology domain. The presence of evolutionarily conserved domains indicates that GRB-7 is likely to perform a basic signaling function. The fact that GRB-7 and HER2 are both overexpressed and bound tightly together suggests that this basic signaling pathway is greatly amplified in certain breast cancers.
3T3 Cells↗
Molecular genetic studies of early breast cancer evolution.
In the past few years there has been an explosion in the number of patients diagnosed with hyperplastic breast disease and in situ breast cancer. Based on epidemiological data, these morphologically defined lesions may be categorized as those with little malignant potential (e.g. typical hyperplasia or proliferative disease without atypia [PDWA], those with significant malignant potential which may already be "initiated" (e.g. atypical ductal hyperplasia [ADH]), and early "transformed" lesions which are malignant but not yet invasive (e.g. ductal carcinoma in situ [DCIS]). They may represent sequential evolutionary stages in the ontogeny of invasive breast cancer, with each morphologically defined stage resulting from accumulating genetic changes culminating in a transformed clonal lineage capable of invasion and metastasis. Using loss-of-heterozygosity (LOH) analysis, we are studying the genetic changes associated with these lesions in archival tissue samples. 50% (6/12) of the proliferative lesions (PDWA and ADH) and 80% of the DCIS shared their LOH patterns with more advanced lesions from the same breast, strongly supporting a precursor/product relationship between these lesion and the cancers they accompany.
Breast Neoplasms↗