Breast Neoplasms: Ljung BM

Carlson RW, Allred DC, Anderson BO, Burstein HJ, Carter WB, Edge SB, Erban JK, Farrar WB, Goldstein LJ, Gradishar WJ, Hayes DF, Hudis CA, Jahanzeb M, Kiel K, Ljung BM, Marcom PK, Mayer IA, McCormick B, Nabell LM, Pierce LJ, Reed EC, Smith ML, Somlo G, Theriault RL, Topham NS, Ward JH, Winer EP, Wolff AC, Anonymous00042. · No affiliation provided · J Natl Compr Canc Netw. · Pubmed #19200416 No free full text.

This publication has no abstract.

Shyyan R, Sener SF, Anderson BO, Garrote LM, Hortobágyi GN, Ibarra JA, Ljung BM, Sancho-Garnier H, Stalsberg H, Anonymous00018. · Department of Surgery, Lviv Regional Cancer Center, Lviv, Ukraine. · Cancer. · Pubmed #18837018 No free full text.

Abstract: A key determinant of breast cancer outcome in any population is the degree to which newly detected cancers can be diagnosed correctly so that therapy can be selected properly and provided in a timely fashion. A multidisciplinary panel of experts reviewed diagnosis guideline tables and discussed core implementation issues and process indicators based on the resource stratification guidelines. Issues were then summarized in the context of 1) clinical assessment, 2) diagnostic breast imaging, 3) tissue sampling, 4) surgical pathology, 5) laboratory tests and metastatic imaging, and 6) the healthcare system. Patient history provides important information for the clinical assessment of breast and comorbid disease that may influence therapy choices. Focused clinical breast examination and complete physical examination provide guidance on the extent of disease, the presence of metastatic disease, and the ability to tolerate aggressive therapeutic regimens. Breast imaging improves preoperative diagnostic assessment and also permits image-guided needle sampling. Diagnostic mammography was not considered mandatory in low- and middle-income countries when resources are lacking. Needle biopsy is preferred to surgical excision for the initial diagnosis of suspicious breast lesions, unless resources are unavailable. Mastectomy should never be used as a method of tissue diagnosis. The availability of predictive tumor markers, especially estrogen receptor testing, is critical when endocrine therapies are available; quality assessment of immunohistochemistry testing is important to avoid false-negative results. Incremental allocation of resources can help address economic disparities and help ensure equity in access to timely diagnosis.

Carlson RW, Moench SJ, Hammond ME, Perez EA, Burstein HJ, Allred DC, Vogel CL, Goldstein LJ, Somlo G, Gradishar WJ, Hudis CA, Jahanzeb M, Stark A, Wolff AC, Press MF, Winer EP, Paik S, Ljung BM, Anonymous00047. · Stanford Hospital and Clinics. · J Natl Compr Canc Netw. · Pubmed #16813731 No free full text.

Abstract: The NCCN HER2 Testing in Breast Cancer Task Force was convened to critically evaluate the ability of the level of HER2 expression or gene amplification in breast cancer tumors to serve as a prognostic and a predictive factor in the metastatic and adjuvant settings, to assess the reliability of the methods of measuring HER2 expression or gene amplification in the laboratory, and to make recommendations regarding the interpretation of test results. The Task Force is a multidisciplinary panel of 24 experts in breast cancer representing the disciplines of medical oncology, pathology, radiation oncology, surgical oncology, epidemiology, and patient advocacy. Invited members included members of the NCCN Breast Cancer Panel and other needed experts selected solely by the NCCN. During a 2-day meeting, individual task force members provided didactic presentations critically evaluating important aspects of HER2 biology and epidemiology: HER2 as a prognostic and predictive factor; results from clinical trials in which trastuzumab was used as a targeted therapy against HER2 in the adjuvant and metastatic settings; the available testing methodologies for HER2, including sensitivity, specificity, and ability to provide prognostic and predictive information; and the principles on which HER2 testing should be based. Each task force member was charged with identifying evidence relevant to their specific expertise and presentation. Following the presentations, an evidence-based consensus approach was used to formulate recommendations relating to the pathologic and clinical application of the evidence to breast cancer patient evaluation and care. In areas of controversy, this process extended beyond the meeting to achieve consensus. The Task Force concluded that accurate assignment of the HER2 status of invasive breast cancer is essential to clinical decision making in the treatment of breast cancer in both adjuvant and metastatic settings. Formal validation and concordance testing should be performed and reported by laboratories performing HER2 testing for clinical purposes. If appropriate quality control/assurance procedures are in place, either immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH) methods may be used. A tumor with an IHC score of 0 or 1+, an average HER2 gene/chromosome 17 ratio of less than 1.8, or an average number of HER2 gene copies/cell of 4 or less as determined by FISH is considered to be HER2 negative. A tumor with an IHC score of 3+, an average HER2 gene/chromosome 17 ratio of greater than 2.2 by FISH, or an average number of HER2 gene copies/cell of 6 or greater is considered HER2 positive. A tumor with an IHC score of 2+ should be further tested using FISH, with HER2 status determined by the FISH result. Tumor samples with an average HER2 gene/chromosome ratio of 1.8 to 2.2 or average number of HER2 gene copies/cell in the range of greater than 4 to less than 6 are considered to be borderline, and strategies to assign the HER2 status of such samples are proposed.

Carlson RW, Anderson BO, Burstein HJ, Cox CE, Edge SB, Farrar WB, Goldstein LJ, Gradishar WJ, Hayes DF, Hudis C, Jahanzeb M, Ljung BM, Marks LB, McCormick B, Nabell LM, Pierce LJ, Reed EC, Silver SM, Smith ML, Somlo G, Theriault RL, Ward JH, Winer EP, Wolff AC, Anonymous00249. · Stanford Hospital & Clinics, USA. · J Natl Compr Canc Netw. · Pubmed #16002000 No free full text.

This publication has no abstract.

Carlson RW, Anderson BO, Burstein HJ, Carter WB, Edge SB, Farrar WB, Goldstein LJ, Gradishar WJ, Hayes DF, Hudis CA, Jahanzeb M, Ljung BM, Kiel K, Marks LB, McCormick B, Nabell LM, Pierce LJ, Reed EC, Silver SM, Smith ML, Somlo G, Theriault RL, Ward JH, Winer EP, Wolff AC. · National Comprehensive Cancer Network · J Natl Compr Canc Netw. · Pubmed #17439758 No free full text.

This publication has no abstract.

Kerlikowske K, Smith-Bindman R, Ljung BM, Grady D. · University of California, San Francisco, General Internal Medicine Section, Department of Veterans Affairs, San Francisco, California 94121, USA. · Ann Intern Med. · Pubmed #12965983 links to  free full text

Abstract: BACKGROUND: Because approximately 1 in 10 women with a breast lump or abnormal mammography result will have breast cancer, a series of decisions must be taken by a primary care practitioner to exclude or establish a diagnosis of breast cancer among these women. PURPOSE: To determine the most accurate and least invasive means to evaluate an abnormal mammography result and a palpable breast abnormality. DATA SOURCE: MEDLINE search (January 1966 to March 2003) for articles and reviews describing the accuracy of clinical examination, biopsy procedures, and radiographic examination for patients with abnormal mammography results or palpable breast abnormalities. STUDY SELECTION: The authors reviewed abstracts and selected articles that provided relevant primary data. Studies were included if 1) mammography, fine-needle aspiration biopsy, or core-needle biopsy was performed before a definitive diagnosis was obtained; 2) the study sample included 100 or more women; and 3) breast cancer status was determined from histopathology review of excisional biopsy specimens, from linkage with a state cancer registry or the Surveillance, Epidemiology, and End Results program, or from clinical follow-up of 95% or more of the study sample. DATA EXTRACTION: One investigator abstracted results. Methods were evaluated for major potential biases, but methodologic scoring was not performed. DATA SYNTHESIS: Likelihood ratios for first screening mammography were 0.1 for the Breast Imaging Reporting and Data System (BI-RADS) assessment category "negative or benign finding," 1.2 for "probably benign finding," 7 for "need additional imaging evaluation," 125 for "suspicious abnormality," and 2200 for "highly suggestive of malignancy." For fine-needle aspiration biopsy of a palpable lump performed by formally trained physicians, the likelihood ratio was infinity for an assessment of "malignant," 2.6 for "atypical/suspicious," and 0.02 for "benign." When diagnostic mammography was used to evaluate a palpable lump or nonpalpable breast abnormality, the positive likelihood ratios were 5.6 and 9.4, and the negative likelihood ratios were 0.15 and 0.19, respectively. CONCLUSIONS: Women whose screening mammography results are interpreted as "suspicious abnormality" or "highly suggestive of malignancy" have a high risk for breast cancer and should undergo core-needle biopsy or needle localization with surgical biopsy. Women whose screening mammography results are interpreted as "need additional imaging evaluation" have a moderate risk for breast cancer and should undergo diagnostic mammography or ultrasonography to decide whether a nonpalpable breast lesion should be biopsied. Women whose screening mammography results are interpreted as "probably benign finding" have a low risk for breast cancer and can undergo follow-up mammography in 6 months. Either fine-needle aspiration biopsy or ultrasonography is recommended as the first diagnostic test of a palpable breast abnormality to distinguish simple cysts from solid masses. Fine-needle aspiration biopsy also allows characterization of a solid mass. Diagnostic mammography does not help determine whether a palpable breast mass should be biopsied and should not affect the decision to perform a biopsy.

Morrow M, Vogel V, Ljung BM, O'Shaughnessy JA. · Lynn Sage Breast Program, Department of Surgery, Northwestern University, Chicago, IL, USA. · J Am Coll Surg. · Pubmed #12022606 No free full text.

This publication has no abstract.

O'Shaughnessy JA, Ljung BM, Dooley WC, Chang J, Kuerer HM, Hung DT, Grant MD, Khan SA, Phillips RF, Duvall K, Euhus DM, King BL, Anderson BO, Troyan SL, Kim J, Veronesi U, Cazzaniga M. · Baylor-Sammons Cancer Center, Dallas, Texas 75246, USA. joyce.o' · Cancer. · Pubmed #11900214 No free full text.

This publication has no abstract.

Brogi E, Robson M, Panageas KS, Casadio C, Ljung BM, Montgomery L. · Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA. · Cancer. · Pubmed #14601086 links to  free full text

Abstract: BACKGROUND: Ductal lavage (DL) is a new method for the sampling of breast epithelium. Data regarding its sensitivity in the detection of epithelial abnormalities, including carcinoma in situ (CIS), remains limited. METHODS: DL was performed in the affected breasts of 26 women undergoing mastectomy for mammary carcinoma and in the clinically normal breast of 4 additional women undergoing risk-reducing mastectomy. After surgery, dye was injected through the microcatheter used for DL. Three cytopathologists independently reviewed all DL slides and the data reflect consensus by at least two reviewers. Interobserver agreement was assessed. The findings in DL samples were correlated with the features of CIS in the mastectomy specimens. RESULTS: Four (14%) of 29 DL samples satisfactory for evaluation showed marked atypia, 10 (34%) showed mild atypia, and 15 (52%) were benign. No DL sample was clearly malignant. Interobserver agreement was good (average kappa = 0.52). Of the DL samples satisfactory for evaluation, 27 had been obtained from 24 breasts containing CIS, which included 18 ductal CIS (DCIS), 3 lobular CIS (LCIS), 2 DCIS and LCIS, and 1 solid CIS with mixed ductal and lobular features. Invasive carcinoma was present in 20 samples. Two DL samples from breasts with extensive LCIS showed mild atypia and injected dye was identified in ducts and lobules involved by LCIS. CONCLUSIONS: DL had low sensitivity for CIS in breasts that also contained invasive carcinoma. The use of DL remains investigational, and close follow-up should be continued for all patients undergoing DL, including those with benign diagnoses.

Masood S, Vass L, Ibarra JA, Ljung BM, Stalsberg H, Eniu A, Carlson RW, Anderson BO, Anonymous00021. · Department of Pathology, College of Medicine, University of Florida, Jacksonville, Florida 32209, USA. · Cancer. · Pubmed #18837021 No free full text.

Abstract: The quality of breast healthcare delivery and the ultimate clinical outcome for patients with breast cancer are directly related to the quality of breast pathology practices within the healthcare system. The Breast Health Global Initiative (BHGI) held its third Global Summit in Budapest, Hungary from October 1 to 4, 2007, bringing together internationally recognized experts to address the implementation of breast healthcare guidelines for the early detection, diagnosis, and treatment in low-income and middle-income countries (LMCs). From this group, a subgroup of experts met to address the specific needs and concerns related to breast pathology program implementation in LMCs. Specific recommendations were made by the group and process indicators identified in the areas of personnel and training, cytology and histopathology interpretation, accuracy of pathology interpretation, pathology reporting, tumor staging, causes of diagnostic errors, use of immunohistochemical markers, and special requirements to facilitate breast conservation therapy. The group agreed that the financial burden of establishing and maintaining breast pathology services is counterbalanced by the cost savings from decreased adverse effects and excessive use of treatment resources that result from incorrect or incomplete pathologic diagnosis. Proper training in breast pathology for pathologists and laboratory technicians is critical and provides the underpinnings of programmatic success for any country at any level of economic wealth.

Adduci KM, Annis CE, DeVries S, Chew KL, Boutin J, Magrane G, Ljung BM, Waldman FM, Esserman LJ. · Department of Surgery, University of California San Francisco, San Francisco, CA 94143-0808, USA. · Cancer. · Pubmed #17474121 links to  free full text

Abstract: BACKGROUND: Ductal lavage (DL) does not routinely identify cytologically malignant cells. For this study, the authors asked whether molecular analyses of DL specimens from women with cancer would identify abnormal cells, even if they appeared cytologically normal. METHODS: DL was performed and yielded fluid in 29 of 45 consenting women who were undergoing breast cancer surgery. Array comparative genomic hybridization (CGH) was performed on the corresponding tumor tissue from 14 women. There was no single, common alteration; thus, bacterial artificial chromosome-specific fluorescence in situ hybridization (FISH) probes were selected based on CGH alterations. RESULTS: FISH copy number changes were detected in tumor sections in 9 women. In the corresponding 9 DL samples, 1 sample was clearly malignant on cytology, 1 showed marked atypia, 1 showed mild atypia, and the rest were benign. Five of the 9 DL samples had epithelial cells that showed genetic changes identical to those observed in the tumor by FISH. The remaining 4 of 9 DL samples that did not show molecular changes were probably (N = 1) or possibly (N = 3) from the same duct as the tumor. CONCLUSIONS: Although only 11% of the DL samples were identified as malignant cytologically, 55% showed molecular changes that were identical to those observed in the tumor. FISH was more sensitive for finding tumor in DL specimens than cytology. However, the ductal system in which the tumor was located did not always yield fluid, limiting the sensitivity of DL. The results from this study showed that genetic changes can be detected in the absence of morphologic changes in cytologically benign cells, but the application will be limited without a better approach for acquiring cells and a common set of probes for detecting molecular abnormalities that are found in breast malignancies.

Chin K, DeVries S, Fridlyand J, Spellman PT, Roydasgupta R, Kuo WL, Lapuk A, Neve RM, Qian Z, Ryder T, Chen F, Feiler H, Tokuyasu T, Kingsley C, Dairkee S, Meng Z, Chew K, Pinkel D, Jain A, Ljung BM, Esserman L, Albertson DG, Waldman FM, Gray JW. · Comprehensive Cancer Center, 2340 Sutter Street, University of California, San Francisco, San Francisco, California 94143. · Cancer Cell. · Pubmed #17157792 No free full text.

Abstract: This study explores the roles of genome copy number abnormalities (CNAs) in breast cancer pathophysiology by identifying associations between recurrent CNAs, gene expression, and clinical outcome in a set of aggressively treated early-stage breast tumors. It shows that the recurrent CNAs differ between tumor subtypes defined by expression pattern and that stratification of patients according to outcome can be improved by measuring both expression and copy number, especially high-level amplification. Sixty-six genes deregulated by the high-level amplifications are potential therapeutic targets. Nine of these (FGFR1, IKBKB, ERBB2, PROCC, ADAM9, FNTA, ACACA, PNMT, and NR1D1) are considered druggable. Low-level CNAs appear to contribute to cancer progression by altering RNA and cellular metabolism.

Fridlyand J, Snijders AM, Ylstra B, Li H, Olshen A, Segraves R, Dairkee S, Tokuyasu T, Ljung BM, Jain AN, McLennan J, Ziegler J, Chin K, Devries S, Feiler H, Gray JW, Waldman F, Pinkel D, Albertson DG. · Department of Epidemiology and Biostatistics, University of California San Francisco, CA 94143, USA. · BMC Cancer. · Pubmed #16620391 links to  free full text

Abstract: BACKGROUND: Genomic DNA copy number aberrations are frequent in solid tumors, although the underlying causes of chromosomal instability in tumors remain obscure. Genes likely to have genomic instability phenotypes when mutated (e.g. those involved in mitosis, replication, repair, and telomeres) are rarely mutated in chromosomally unstable sporadic tumors, even though such mutations are associated with some heritable cancer prone syndromes. METHODS: We applied array comparative genomic hybridization (CGH) to the analysis of breast tumors. The variation in the levels of genomic instability amongst tumors prompted us to investigate whether alterations in processes/genes involved in maintenance and/or manipulation of the genome were associated with particular types of genomic instability. RESULTS: We discriminated three breast tumor subtypes based on genomic DNA copy number alterations. The subtypes varied with respect to level of genomic instability. We find that shorter telomeres and altered telomere related gene expression are associated with amplification, implicating telomere attrition as a promoter of this type of aberration in breast cancer. On the other hand, the numbers of chromosomal alterations, particularly low level changes, are associated with altered expression of genes in other functional classes (mitosis, cell cycle, DNA replication and repair). Further, although loss of function instability phenotypes have been demonstrated for many of the genes in model systems, we observed enhanced expression of most genes in tumors, indicating that over expression, rather than deficiency underlies instability. CONCLUSION: Many of the genes associated with higher frequency of copy number aberrations are direct targets of E2F, supporting the hypothesis that deregulation of the Rb pathway is a major contributor to chromosomal instability in breast tumors. These observations are consistent with failure to find mutations in sporadic tumors in genes that have roles in maintenance or manipulation of the genome.

Brogi E, Miller MJ, Casadio C, Ljung BM, Montgomery L. · Cytology Laboratory--Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA. · Diagn Cytopathol. · Pubmed #16299749 No free full text.

Abstract: Ductal lavage (DL) is a new procedure for sampling of the mammary epithelium, but experience with this technique remains limited. We compared the findings in paired DL and fine-needle aspiration (FNA) specimens obtained from patients with breast carcinoma. Four reviewers evaluated all DL samples. Two reviewers also examined the FNA material and compared cellular composition and morphologic findings in paired samples. DL and FNA samples from six patients were satisfactory for evaluation. Two DL samples showed marked atypia, one showed mild atypia, and two were benign; there was no agreement in one case (mild atypia vs. benign). Overall, the atypical cells in DL samples resembled those in the paired FNA material, but low degree of cytologic atypia and relative paucity of atypical cells limited their correct identification. The interpretation of DL samples is more challenging than that of FNA material, but similar criteria apply. To increase the sensitivity of DL, the number of epithelial cells required for a satisfactory sample should be higher than previously set.

Cummings SR, Lee JS, Lui LY, Stone K, Ljung BM, Cauleys JA. · California Pacific Medical Center, Coordinating Center, Suite 600, 74 New Montgomery Street, San Francisco, CA 94105, USA. · Cancer Epidemiol Biomarkers Prev. · Pubmed #15894651 links to  free full text

Abstract: OBJECTIVE: Antiestrogens reduce the risk of estrogen receptor-positive (ER+) but not ER-negative (ER-) breast cancer. Women at high risk of ER+ cancer would be the most likely to benefit from these treatments, but the best approach to predicting ER+ cancer is uncertain. METHODS: We prospectively assessed putative risk factors for breast cancer and archived serum at -190 degrees C from a community-based cohort of 7,676 women ages > or =65 years who had no history of breast cancer. Follow-up for breast cancer over 10.5 years was 99% complete. Using a case-cohort design, we measured baseline levels of estradiol and testosterone in 196 cases of invasive ER+ cancer and 378 randomly selected controls. RESULTS: Women whose testosterone level in highest two quintiles had a 4-fold increased risk of ER+ breast cancer (P < 0.0001). High estradiol concentration also indicated an increased risk but was not a significant predictor after adjustment for testosterone. Women with >16 years of education had a 2.1 times increased risk (P = 0.03) of ER+ cancer, but no other risk factors were significantly related to an increased risk of ER+ cancer. Women with a family history of breast cancer had a 2.9-fold increased risk of ER- cancer (P = 0.002) but no increased risk of ER+ cancer (relative hazard = 1.2, 0.8-1.8). CONCLUSIONS: High serum testosterone and advanced education predicted ER+ breast cancer. If confirmed, high testosterone level may be more accurate than family history of breast cancer and other conventional risk factors for identifying older women who are most likely to benefit from antiestrogen chemoprevention.

Khan SA, Wiley EL, Rodriguez N, Baird C, Ramakrishnan R, Nayar R, Bryk M, Bethke KB, Staradub VL, Wolfman J, Rademaker A, Ljung BM, Morrow M. · Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago IL, USA. · J Natl Cancer Inst. · Pubmed #15494601 links to  free full text

Abstract: BACKGROUND: Ductal lavage has the potential to detect cancer by sampling breast epithelium in asymptomatic high-risk women. To assess the utility of ductal lavage as a cancer diagnostic test, we investigated the association between ductal lavage cytologic findings and histologic findings in women with known breast cancer undergoing mastectomy. METHODS: Ductal lavage was performed in the operating room before mastectomy on 44 breasts from 32 women with known cancer and on eight breasts from seven women undergoing prophylactic mastectomy, two with occult malignancy. If the ductal lavage sample from one or more ducts contained enough epithelial cells for a cytologic diagnosis, lavaged ducts were injected with a mixture of colored dye, gelatin, and a radiographic contrast compound after mastectomy, and breast tissue was radiographed and sectioned. Histologic findings in ducts with and without dye were recorded. Associations between cytologic results and histologic results were examined by univariate and multivariable analyses. RESULTS: At least one duct was lavaged in 36 breasts (mean = 1.4 ducts per breast); all histologic and cytologic procedures were completed in 28 breasts and in 39 ducts. Markedly atypical or malignant cytology was found in five cancer-containing breasts. In 39 ducts with complete cytologic and histologic data and when marked atypia or malignant cells defined a positive cytologic test, sensitivity was 43% (95% confidence interval [CI] = 23% to 72%), specificity was 96% (95% CI = 86% to 100%), and accuracy was 77% (95% CI = 63% to 89%). When mild or marked atypia or malignant cells defined a positive cytologic test, sensitivity was 79% (95% CI = 57% to 96%), specificity was 64% (95% CI = 46% to 83%), and accuracy was 69% (95% CI = 55% to 83%). When all 31 cytologically evaluable breasts were analyzed, sensitivity was 17% (95% CI = 7% to 35%), specificity was 100% (95% CI = 5% to 100%), and accuracy was 19% (95% CI = 9% to 38%). CONCLUSION: In breasts with cancer, ductal lavage appears to have low sensitivity and high specificity for cancer detection, possibly because cancer-containing ducts fail to yield fluid or have benign or mildly atypical cytology.

Meng ZH, Ben Y, Li Z, Chew K, Ljung BM, Lagios MD, Dairkee SH. · California Pacific Medical Center, San Francisco, California 94115, USA. · Genes Chromosomes Cancer. · Pubmed #15334544 No free full text.

Abstract: In the search for early deletion targets in sporadic breast cancer, the analysis of TP53, BRCA1, BRCA2, and ATM revealed loss of heterozygosity (LOH) in tumor cells at 1 or more genes in 18 of 24 cases examined. Notably, in more than 60% of such tumors, LOH was detectable in morphologically normal terminal ductal lobular units (TDLUs) adjacent to carcinoma (LOHint). At BRCA2 and ATM, LOHint was most frequent, particularly in TDLUs of women <or= 50 years old (7 of 10). In a novel preneoplastic model system, declining expression levels observed with increasing passage in culture supported the postulate that during the acquisition of continuous growth, elimination of these genes at an early stage confers a distinct selective advantage. The intimate role of these genes in DNA repair and their early deletion has implications for the possible transforming effects of DNA-damaging agents on unexcised breast tissue harboring LOHint within breast cancer patients.

Chin K, de Solorzano CO, Knowles D, Jones A, Chou W, Rodriguez EG, Kuo WL, Ljung BM, Chew K, Myambo K, Miranda M, Krig S, Garbe J, Stampfer M, Yaswen P, Gray JW, Lockett SJ. · Department of Laboratory Medicine and Comprehensive Cancer Center, University of California San Francisco, California, USA. · Nat Genet. · Pubmed #15300252 No free full text.

Abstract: Transition through telomere crisis is thought to be a crucial event in the development of most breast carcinomas. Our goal in this study was to determine where this occurs in the context of histologically defined breast cancer progression. To this end, we assessed genome instability (using fluorescence in situ hybridization) and other features associated with telomere crisis in normal ductal epithelium, usual ductal hyperplasia, ductal carcinoma in situ and invasive cancer. We modeled this process in vitro by measuring these same features in human mammary epithelial cell cultures during ZNF217-mediated transition through telomere crisis and immortalization. Taken together, the data suggest that transition through telomere crisis and immortalization in breast cancer occurs during progression from usual ductal hyperplasia to ductal carcinoma in situ.

Hwang ES, DeVries S, Chew KL, Moore DH, Kerlikowske K, Thor A, Ljung BM, Waldman FM. · Department of Surgery, University of California San Francisco, San Francisco, California 94115, USA. · Clin Cancer Res. · Pubmed #15297420 links to  free full text

Abstract: PURPOSE: Ductal carcinoma in situ (DCIS) is thought to be a nonobligate precursor of invasive cancer. Genomic changes specific to pure DCIS versus invasive cancer, as well as alterations unique to individual DCIS subtypes, have not been fully defined. EXPERIMENTAL DESIGN: Chromosomal copy number alterations were examined by comparative genomic hybridization in 34 cases of pure DCIS and compared with 12 cases of paired synchronous DCIS and invasive ductal cancer, as well as to 146 additional cases of invasive breast cancer of ductal or lobular histology. Genomic differences between high-grade and low/intermediate-grade DCIS, as well as between pure DCIS and invasive cancer, were identified. RESULTS: Pure DCIS showed almost the same degree of chromosomal instability as invasive ductal cancers. A higher proportion of low/intermediate-grade versus high-grade DCIS had loss of 16q (65 versus 12%, respectively; P = 0.002). When compared with lower grade DCIS, high-grade DCIS exhibited more frequent gain of 17q (65 versus 41%; P = 0.15) and higher frequency loss of 8p (77 versus 41%; P = 0.04). Chromosomal alterations in those cases with synchronous DCIS and invasive ductal cancer showed a high degree of shared changes within the two components. CONCLUSIONS: DCIS is genetically advanced, showing a similar degree of chromosomal alterations as invasive ductal cancer. The pattern of alterations differed between high- and low/intermediate-grade DCIS, supporting a model in which different histological grades of DCIS are associated with distinct genomic changes. These regions of chromosomal alterations may be potential targets for treatment and/or markers of prognosis.

Kerlikowske K, Molinaro A, Cha I, Ljung BM, Ernster VL, Stewart K, Chew K, Moore DH, Waldman F. · Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA. · J Natl Cancer Inst. · Pubmed #14625260 links to  free full text

Abstract: BACKGROUND: Clinical and histopathologic characteristics that may predict risks of recurrence in women with ductal carcinoma in situ (DCIS) have not been consistently identified. We identified factors associated with recurrence as DCIS versus invasive breast cancer and determined the 5-year absolute risks of recurrence as a function of these factors. METHODS: We conducted a population-based cohort study among 1036 women in the San Francisco Bay Area who were aged 40 years or older when diagnosed with DCIS and treated by lumpectomy alone from January 1983 through December 1994. Standardized pathology reviews were conducted to determine disease recurrence, defined as DCIS or invasive breast cancer diagnosed in the ipsilateral breast containing the initial DCIS lesion or at a distant site more than 6 months after the initial diagnosis and treatment of DCIS. Conditional logistic regression models were used to determine factors associated with recurrence. All statistical significance tests were two-sided. RESULTS: During a median follow-up of 77.9 months, 209 women (20.2%) experienced a recurrence. Overall, the 5-year risks of recurrence as invasive cancer and as DCIS were 8.2% (95% confidence interval [CI] = 6.6% to 9.8%) and 11.7% (95% CI = 9.9% to 13.3%), respectively. The 5-year risks of recurrence as invasive cancer and as DCIS were 4.8% (95% CI = 3.7% to 6.8%) and 4.8% (95% CI = 3.8% to 5.8%), respectively, for women with low-nuclear-grade DCIS; 11.8% (95% CI = 9.9% to 14.1%) and 17.1% (95% CI = 15.5% to 18.7%), respectively, for women with high-nuclear-grade DCIS; 11.6% (95% CI = 11.3% to 12.0%) and 8.6% (95% CI = 7.1% to 10.2%), respectively, for women whose initial DCIS lesion was detected by palpation; and 6.6% (95% CI = 6.2% to 7.1%) and 14.1% (95% CI = 11.4% to 17.8%), respectively, for women with DCIS detected by mammography alone. High- (versus low-) nuclear-grade DCIS lesions and detection of the initial DCIS lesion by palpation (versus mammography) were associated with recurrence as invasive cancer. High- (versus low-) nuclear-grade lesions; resection margins that were positive, uncertain, or less than 10 mm disease-free (versus > or = 10 mm disease-free); and age 40-49 years at diagnosis (versus > or =50 years) were associated with recurrence as DCIS. CONCLUSIONS: Nuclear grade is strongly associated with recurrence but not with the type of recurrence. Women with high-nuclear-grade DCIS or DCIS detected by palpation who are treated by lumpectomy alone are at relatively high risk of having an invasive breast cancer recurrence, compared with women with low-nuclear-grade or mammographically detected DCIS, and may be appropriate candidates for additional treatment.

Cauley JA, Zmuda JM, Danielson ME, Ljung BM, Bauer DC, Cummings SR, Kuller LH. · Department of Epidemiology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. · Epidemiology. · Pubmed #14569192 No free full text.

Abstract: BACKGROUND: Women who metabolize a large proportion of their estrogen via the 16alpha hydroxylation pathway could be at a higher risk of breast cancer. The objective of this study was to test the hypothesis that serum concentrations of 2-hydroxyestrone (2-OHE1) and 16alpha-hydroxyestrone (16alpha-OHE1), as well as their ratio, predict the risk of breast cancer in older women. METHODS: We performed a case-cohort study of 272 women with confirmed incident breast cancer and 291 controls chosen randomly from the cohort. Estrogen metabolites were measured in serum collected at the baseline examination and stored at -120 degrees C. Incident breast cancers were confirmed by medical records and pathology reports during an average follow-up of 8.7 years. RESULTS: Mean concentrations of 2-OHE1 and 16alpha-OHE1, adjusted for age and body mass index, were 3% to 4% higher in cases compared with controls: 2-OHE1 was 176 pg/mL and 169 pg/mL and 16alpha-OHE1 was 233 pg/mL and 226 pg/mL in cases and controls, respectively. There was, however, no difference in the ratio of 2-OHE1 to 16alpha-OHE1. The risk of breast cancer in women with the highest quartile of this ratio compared with those in the lowest quartile was 1.17 (95% confidence interval = 0.73-1.87). CONCLUSION: The study results do not support the hypothesis that the ratio of 2-OHE1 to 16alpha-OHE1 predicts breast cancer risk.

Li Z, Meng ZH, Sayeed A, Shalaby R, Ljung BM, Dairkee SH. · Geraldine Brush Cancer Research Institute, California Pacific Medical Center, San Francisco 94115, USA. · Cancer Res. · Pubmed #12384566 links to  free full text

Abstract: Toward the goal of identifying early genetic losses, which mediate the release of human breast epithelium from replicative suppression leading to cellular immortalization, we have used a newly developed in vitro model system. This system consists of epithelial cultures derived from noncancerous breast tissue, treated with the chemical carcinogen N-ethyl-N-nitrosourea, and continuously passaged to yield cell populations culminating in the immortal phenotype. Genome-wide allelotyping of early passage N-ethyl-N-nitrosourea-exposed cell populations revealed aberrations at >10% (18 of 169) loci examined. Allelic losses encompassing chromosomes 6q24-6q27, implicating immortalization-associated candidate genes, hZAC and SEN6, occurred in two independently derived cell lines before the Hayflick limit. Additional LOH sites were present in one cell line at 3p11-3p26, 11p15, and 20p12-13. Allelic losses reported in this cell line preceded detectable levels of telomerase activity and the occurrence of p53-related aberrations. Information gained from the search for early immortalization-associated genetic deletions in cultured cells was applied in a novel approach toward the analysis of morphologically normal terminal ductal lobular units microdissected from 20 cases of ductal carcinoma in situ. Notably, clonal allelic losses at chromosome 3p24 and 6q24 were an early occurrence in adjoining terminal ductal lobular units of a proportion of primary tumors, which displayed loss of heterozygosity (3 of 11 and 3 of 6, respectively). The biological insights provided by the new model system reported here strongly suggest that early allelic losses delineated in immortalized cultures and validated in vivo could serve as surrogate endpoints to assist in the identification and intervention of high-risk benign breast tissue, which sustains the potential for continuous proliferation.

Li Z, Moore DH, Meng ZH, Ljung BM, Gray JW, Dairkee SH. · Geraldine Brush Cancer Research Institute, California Pacific Medical Center, San Francisco, California 94115, USA. · Cancer Res. · Pubmed #11861372 links to  free full text

Abstract: Allelic losses characteristic of tumor cells, when displayed by morphologically normal terminal ductal lobular units (TDLUs) adjacent to carcinoma [G. Deng et al., Science (Wash. DC), 274: 2057-2059, 1996], may indicate an extended field of increased cancer susceptibility within the affected breast tissue. We investigated this possibility by asking whether the presence of loss of heterozygosity (LOH) at chromosome 3p11-26 in histologically normal TDLUs (3pLOHn) could lead to an increased risk of local tumor recurrence. We assessed LOHs in normal TDLUs adjacent to 48 informative cases of early-stage invasive breast cancer samples and found 3pLOHn in approximately 25% (13 of 48) of patients whose tumors had 3pLOH in this region. Our analyses suggest that the most frequent region of LOH is localized at 3p24.3. We also demonstrate, using a Cox proportional hazards regression model, that the presence of 3pLOHn was the only variable significantly related to local tumor recurrence, leading to a 3.9-5.2-fold increase in the hazard ratio (P < 0.05). The time to recurrence was longer in such cases than in those without 3pLOHn, suggesting de novo tumor development. These data provide a strong rationale to assess histologically normal breast tissue at the margins of surgically excised cancers for molecular predictors of local recurrence after breast-conserving treatment.

Dooley WC, Ljung BM, Veronesi U, Cazzaniga M, Elledge RM, O'Shaughnessy JA, Kuerer HM, Hung DT, Khan SA, Phillips RF, Ganz PA, Euhus DM, Esserman LJ, Haffty BG, King BL, Kelley MC, Anderson MM, Schmit PJ, Clark RR, Kass FC, Anderson BO, Troyan SL, Arias RD, Quiring JN, Love SM, Page DL, King EB. · Institute for Breast Health, University of Oklahoma Health Sciences Center, Oklahoma City, 73104, USA. · J Natl Cancer Inst. · Pubmed #11698566 links to  free full text

Abstract: BACKGROUND: Breast cancer originates in breast epithelium and is associated with progressive molecular and morphologic changes. Women with atypical breast ductal epithelial cells have an increased relative risk of breast cancer. In this study, ductal lavage, a new procedure for collecting ductal cells with a microcatheter, was compared with nipple aspiration with regard to safety, tolerability, and the ability to detect abnormal breast epithelial cells. METHODS: Women at high risk for breast cancer who had nonsuspicious mammograms and clinical breast examinations underwent nipple aspiration followed by lavage of fluid-yielding ducts. All statistical tests were two-sided. RESULTS: The 507 women enrolled included 291 (57%) with a history of breast cancer and 199 (39%) with a 5-year Gail risk for breast cancer of 1.7% or more. Nipple aspirate fluid (NAF) samples were evaluated cytologically for 417 women, and ductal lavage samples were evaluated for 383 women. Adequate samples for diagnosis were collected from 111 (27%) and 299 (78%) women, respectively. A median of 13,500 epithelial cells per duct (range, 43-492,000 cells) was collected by ductal lavage compared with a median of 120 epithelial cells per breast (range, 10-74,300) collected by nipple aspiration. For ductal lavage, 92 (24%) subjects had abnormal cells that were mildly (17%) or markedly (6%) atypical or malignant (<1%). For NAF, corresponding percentages were 6%, 3%, and fewer than 1%. Ductal lavage detected abnormal intraductal breast cells 3.2 times more often than nipple aspiration (79 versus 25 breasts; McNemar's test, P<.001). No serious procedure-related adverse events were reported. CONCLUSIONS: Large numbers of ductal cells can be collected by ductal lavage to detect atypical cellular changes within the breast. Ductal lavage is a safe and well-tolerated procedure and is a more sensitive method of detecting cellular atypia than nipple aspiration.

Ljung BM, Drejet A, Chiampi N, Jeffrey J, Goodson WH, Chew K, Moore DH, Miller TR. · Department of Pathology, University of California, San Francisco, California 94143-1656, USA. · Cancer. · Pubmed #11507700 links to  free full text

Abstract: BACKGROUND: Fine-needle aspiration biopsy (FNAB) has been used with variable success as a diagnostic test for benign and malignant breast lesions. The goal of this study was to examine the effects of training physicians in the fine-needle aspiration sampling-technique on the diagnostic accuracy of FNAB of palpable breast masses. The settings for this study were private physicians' offices and university clinics of primary care physicians, surgeons, and cytopathologists. METHODS: We reviewed 1043 consecutive FNAB specimens of the breast obtained during 1 year (1992): 729 FNABs were performed by formally trained physicians (at least 150 FNABs performed previously under supervision during fellowship training or the equivalent) who had done at least 100 FNABs during the year; 314 FNABs were performed by physicians without formal training who had done a median of only 2 FNABs during the year (range, 1-43 FNABs). All FNAB specimens were reviewed microscopically and evaluated for cellularity and type of material present, for diagnostic accuracy, and for the rate of surgical intervention. A minimum of 2 years of follow-up was obtained by matching all cases to the population-based Northern California Cancer Registry. FNAB specimens were correlated with histologic specimens when they were available. RESULTS: Using FNAB, the formally trained physicians missed 2% of cancers, whereas the physicians without formal training missed 25%. Among the patients with benign lesions seen by the formally trained physicians, 8% went on to surgery, whereas 30% of those seen by physicians without formal training did so. Specimens obtained by the formally trained physicians were significantly more cellular and were significantly less likely to be nondiagnostic. CONCLUSIONS: FNAB, when performed by physicians who are well trained in the technique, is a highly accurate, cost-effective diagnostic method that carries minimal morbidity and could replace a large number of surgical biopsies. When performed by physicians without adequate training, FNAB is often misleading and potentially harmful.