Evaluating wait times from screening to breast cancer diagnosis among women undergoing organised assessment vs usual care.

BACKGROUND: Timely coordinated diagnostic assessment following an abnormal screening mammogram reduces patient anxiety and may optimise breast cancer prognosis. Since 1998, the Ontario Breast Screening Program (OBSP) has offered organised assessment through Breast Assessment Centres (BACs). For OBSP women seen at a BAC, an abnormal mammogram is followed by coordinated referrals through the use of navigators for further imaging, biopsy, and surgical consultation as indicated. For OBSP women seen through usual care (UC), further diagnostic imaging is arranged directly from the screening centre and/or through their physician; results must be communicated to the physician who is then responsible for arranging any necessary biopsy and/or surgical consultation. This study aims to evaluate factors associated with diagnostic wait times for women undergoing assessment through BAC and UC. METHODS: Of the 2 147 257 women aged 50-69 years screened in the OBSP between 1 January 2002 and 31 December 2009, 155 866 (7.3%) had an abnormal mammogram. A retrospective design identified two concurrent cohorts of women diagnosed with screen-detected breast cancer at a BAC (n=4217; 47%) and UC (n=4827; 53%). Multivariable logistic regression analyses examined associations between wait times and assessment and prognostic characteristics by pathway. A two-sided 5% significance level was used. RESULTS: Screened women with breast cancer were two times more likely to be diagnosed within 7 weeks when assessed through a BAC vs UC (OR=1.91, 95% CI=1.73-2.10). In addition, compared with UC, women assessed through a BAC were significantly more likely to have their first assessment procedure within 3 weeks of their abnormal mammogram (OR=1.25, 95% CI=1.12-1.39), ⩽3 assessment procedures (OR=1.54, 95% CI=1.41-1.69), ⩽2 assessment visits (OR=1.86, 95% CI=1.70-2.05), and ⩾2 procedures per visit (OR=1.41, 95% CI=1.28-1.55). Women diagnosed through a BAC were also more likely than those in UC to have imaging (OR=1.99, 95% CI=1.44-2.75) or a biopsy (OR=3.69, 95% CI=2.64-5.15) vs consultation only at their first assessment visit, and two times more likely to have a core or FNA biopsy than a surgical biopsy (OR=2.08, 95% CI=1.81-2.40). Having ⩽2 assessment visits was more likely to reduce time to diagnosis for women assessed through a BAC compared with UC (BAC OR=10.58, 95% CI=8.96-12.50; UC OR=4.47, 95% CI=3.94-5.07), as was having ⩽3 assessment procedures (BAC OR=4.97, 95% CI=4.26-5.79; UC OR=2.95, 95% CI=2.61-3.33). Income quintile affected wait times only in women diagnosed in UC, with those in the two highest quintiles more likely to receive a diagnosis in 7 weeks. CONCLUSIONS: Women with screen-detected breast cancer in OBSP were more likely to have shorter wait times if they were diagnosed through organised assessment. This might be as a result of women diagnosed through a BAC having more procedures per visit, procedures scheduled in shorter intervals, and imaging or biopsy on their first visit. Given the significant improvement in timeliness to diagnosis, women with abnormal mammograms should be managed through organised assessment.

Diagnostic concordance among pathologists interpreting breast biopsy specimens.

IMPORTANCE: A breast pathology diagnosis provides the basis for clinical treatment and management decisions; however, its accuracy is inadequately understood. OBJECTIVES: To quantify the magnitude of diagnostic disagreement among pathologists compared with a consensus panel reference diagnosis and to evaluate associated patient and pathologist characteristics. DESIGN, SETTING, AND PARTICIPANTS: Study of pathologists who interpret breast biopsies in clinical practices in 8 US states. EXPOSURES: Participants independently interpreted slides between November 2011 and May 2014 from test sets of 60 breast biopsies (240 total cases, 1 slide per case), including 23 cases of invasive breast cancer, 73 ductal carcinoma in situ (DCIS), 72 with atypical hyperplasia (atypia), and 72 benign cases without atypia. Participants were blinded to the interpretations of other study pathologists and consensus panel members. Among the 3 consensus panel members, unanimous agreement of their independent diagnoses was 75%, and concordance with the consensus-derived reference diagnoses was 90.3%. MAIN OUTCOMES AND MEASURES: The proportions of diagnoses overinterpreted and underinterpreted relative to the consensus-derived reference diagnoses were assessed. RESULTS: Sixty-five percent of invited, responding pathologists were eligible and consented to participate. Of these, 91% (N = 115) completed the study, providing 6900 individual case diagnoses. Compared with the consensus-derived reference diagnosis, the overall concordance rate of diagnostic interpretations of participating pathologists was 75.3% (95% CI, 73.4%-77.0%; 5194 of 6900 interpretations). Among invasive carcinoma cases (663 interpretations), 96% (95% CI, 94%-97%) were concordant, and 4% (95% CI, 3%-6%) were underinterpreted; among DCIS cases (2097 interpretations), 84% (95% CI, 82%-86%) were concordant, 3% (95% CI, 2%-4%) were overinterpreted, and 13% (95% CI, 12%-15%) were underinterpreted; among atypia cases (2070 interpretations), 48% (95% CI, 44%-52%) were concordant, 17% (95% CI, 15%-21%) were overinterpreted, and 35% (95% CI, 31%-39%) were underinterpreted; and among benign cases without atypia (2070 interpretations), 87% (95% CI, 85%-89%) were concordant and 13% (95% CI, 11%-15%) were overinterpreted. Disagreement with the reference diagnosis was statistically significantly higher among biopsies from women with higher (n = 122) vs lower (n = 118) breast density on prior mammograms (overall concordance rate, 73% [95% CI, 71%-75%] for higher vs 77% [95% CI, 75%-80%] for lower, P < .001), and among pathologists who interpreted lower weekly case volumes (P < .001) or worked in smaller practices (P = .034) or nonacademic settings (P = .007). CONCLUSIONS AND RELEVANCE: In this study of pathologists, in which diagnostic interpretation was based on a single breast biopsy slide, overall agreement between the individual pathologists' interpretations and the expert consensus-derived reference diagnoses was 75.3%, with the highest level of concordance for invasive carcinoma and lower levels of concordance for DCIS and atypia. Further research is needed to understand the relationship of these findings with patient management.

Understanding diagnostic variability in breast pathology: lessons learned from an expert consensus review panel.

AIMS: To gain a better understanding of the reasons for diagnostic variability, with the aim of reducing the phenomenon. METHODS AND RESULTS: In preparation for a study on the interpretation of breast specimens (B-PATH), a panel of three experienced breast pathologists reviewed 336 cases to develop consensus reference diagnoses. After independent assessment, cases coded as diagnostically discordant were discussed at consensus meetings. By the use of qualitative data analysis techniques, transcripts of 16 h of consensus meetings for a subset of 201 cases were analysed. Diagnostic variability could be attributed to three overall root causes: (i) pathologist-related; (ii) diagnostic coding/study methodology-related; and (iii) specimen-related. Most pathologist-related root causes were attributable to professional differences in pathologists' opinions about whether the diagnostic criteria for a specific diagnosis were met, most frequently in cases of atypia. Diagnostic coding/study methodology-related root causes were primarily miscategorizations of descriptive text diagnoses, which led to the development of a standardized electronic diagnostic form (BPATH-Dx). Specimen-related root causes included artefacts, limited diagnostic material, and poor slide quality. After re-review and discussion, a consensus diagnosis could be assigned in all cases. CONCLUSIONS: Diagnostic variability is related to multiple factors, but consensus conferences, standardized electronic reporting formats and comments on suboptimal specimen quality can be used to reduce diagnostic variability.

Digitized whole slides for breast pathology interpretation: current practices and perceptions.

Digital whole slide imaging (WSI) is an emerging technology for pathology interpretation; however, little is known about pathologists' practice patterns or perceptions regarding WSI. A national sample (N = 252) of pathologists from New Hampshire, Vermont, Washington, Oregon, Arizona, Alaska, Maine, and Minnesota were surveyed in this cross-sectional study (2011-2013). The survey included questions on pathologists' experience, WSI practice patterns, and perceptions using a six-point Likert scale. Agreement was summarized with descriptive statistics to characterize pathologists' use and perceptions of WSI. The majority of participating pathologists were males (63%) between 40 and 59 years of age (70%) and not affiliated with an academic medical center (72%). Experience with WSI was reported by 49%. Types of use reported included CME/board exams/teaching (28%), tumor board/clinical conference (22%), archival purposes (6%), consultative diagnosis (4%), research (4%), and other uses (12%). Most respondents (79%) agreed that accurate diagnoses can be made with this technology, and that WSI is useful for obtaining a second opinion (88%). However, 78% of pathologists agreed that digital slides are too slow for routine clinical interpretation. Fifty-nine percent agreed that the benefits of WSI outweigh concerns. The respondents were equally split as to whether they would like to adopt WSI (51%) or not (49%). About half of pathologists reported experience with the WSI technology, largely for CME, licensure/board exams, and teaching. Positive perceptions regarding WSI slightly outweigh negative perceptions. Understanding practice patterns with WSI as dissemination advances may facilitate concordance of perceptions with adoption of the technology.

Clinical-pathologic significance of cancer stem cell marker expression in familial breast cancers.

Human breast cancer cells with a CD44(+)/CD24(-/low) or ALDH1+ phenotype have been demonstrated to be enriched for cancer stem cells (CSCs) using in vitro and in vivo techniques. The aim of this study was to determine the association between CD44(+)/CD24(-/low) and ALDH1 expression with clinical-pathologic tumor characteristics, tumor molecular subtype, and survival in a well characterized collection of familial breast cancer cases. 364 familial breast cancers from the Ontario Familial Breast Cancer Registry (58 BRCA1-associated, 64 BRCA2-associated, and 242 familial non-BRCA1/2 cancers) were studied. Each tumor had a centralized pathology review performed. TMA sections of all tumors were analyzed for the expression of ER, PR, HER2, CK5, CK14, EGFR, CD44, CD24, and ALDH1. The Chi square test or Fisher's exact test was used to analyze the marker associations with clinical-pathologic tumor variables, molecular subtype and genetic subtype. Analyses of the association of overall survival (OS) with marker status were conducted using Kaplan-Meier plots and log-rank tests. The CD44(+)/CD24(-/low) and ALDH1+ phenotypes were identified in 16% and 15% of the familial breast cancer cases, respectively, and associated with high-tumor grade, a high-mitotic count, and component features of the medullary type of breast cancer. CD44(+)/CD24(-/low) and ALDH1 expression in this series were further associated with the basal-like molecular subtype and the CD44(+)/CD24(-/low) phenotype was independently associated with BRCA1 mutational status. The currently accepted breast CSCs markers are present in a minority of familial breast cancers. Whereas the presence of these markers is correlated with several poor prognostic features and the basal-like subtype of breast cancer, they do not predict OS.

Elevated expression of podocalyxin is associated with lymphatic invasion, basal-like phenotype, and clinical outcome in axillary lymph node-negative breast cancer.

Lymphatic invasion (LVI) is associated with disease recurrence in axillary node-negative (ANN) breast cancer. Using gene expression profiling of 105 ANN tumors, we found that podocalyxin (PODXL) was more highly expressed in tumors with LVI (LVI+) than in those without LVI (LVI-). Differences in PODXL expression were validated using real-time polymerase chain reaction as well as by immunohistochemistry in an independent set of 652 tumors on tissue microarrays. Disease-free survival (DFS) analyses were conducted for association of high PODXL protein expression with risk of distant recurrence overall and within breast cancer subtypes using both Cox and cure-rate models. High PODXL expression was associated with poor prognosis features including large tumor size, high histological grade, estrogen and progesterone receptor negativity, and with clinical alterations characteristic of the basal-like breast cancer phenotype. Surprisingly, despite having other poor prognosis characteristics, women with high PODXL expressing tumors had better long-term DFS in multivariate analysis with traditional clinicopathologic factors including LVI and HER2 status (P = 0.001). PODXL has the potential to be a useful biomarker for identifying good prognosis patients in characteristically poor prognosis breast cancer groups and may impact treatment of women with this disease.

TIMP-1 in combination with HER2 and TOP2A for prediction of benefit from adjuvant anthracyclines in high-risk breast cancer patients.

HER2 amplification, TOP2A aberrations, and absence of tissue inhibitor of metalloproteinase (TIMP-1) expression in breast carcinomas have been shown to be associated with incremental benefit from anthracycline-containing adjuvant chemotherapy, and this study was undertaken to validate these findings in a similar, but independent, randomized clinical trial. TIMP-1 was examined by immunohistochemistry in archival tumor tissue from 403 of 716 premenopausal high-risk patients with known HER2 and TOP2A status who were randomized to cyclophosphamide, epirubicin, and fluorouracil (CEF) or cyclophosphamide, methotrexate, and fluorouracil (CMF) in the MA.5 trial. Ninety-eight (24%) patients had no TIMP-1 staining of tumor cells, 27% were HER2 amplified, and 18% were TOP2A aberrant. Forty-four percentage was classified as HT responsive (HER2 amplified and/or TIMP-1 negative) and 37% as 2T responsive (TOP2A aberrant and/or TIMP-1 negative). There was no heterogeneity in treatment effect of CEF versus CMF according to TIMP-1. In HT-responsive patients, CEF was superior to CMF with an improved RFS (adjusted HR, 0.64; 95% CI, 0.42-0.97), but this was not significant for OS (adjusted HR, 0.66; 95% CI, 0.42-1.04). A significant HT profile versus treatment interaction was detected for OS (P = 0.03). In 2T-responsive patients, CEF seemed to improve RFS compared to CMF (adjusted HR, 0.67; 95% CI, 0.43-1.03) and improved OS (adjusted HR, 0.58; 95% CI, 0.36-0.93). A significant 2T profile versus treatment interaction was detected for OS (P = 0.01). With this study, we validate a more substantial reduction in mortality by CEF compared to CMF in patients with an HT- or 2T-responsive profile; however, we could not show a similarly significant reduction in RFS events, where a benefit of CEF over CMF was found irrespective of TIMP-1 status. Further studies are necessary before the HT and 2T profiles may be used to direct the use of anthracyclines.

Chromosome 17 centromere (CEP17) duplication as a predictor of anthracycline response: evidence from the NCIC Clinical Trials Group (NCIC CTG) MA.5 Trial.

HER2 gene amplification and topoisomerase IIα gene (TOP2A) alteration have been associated with increased benefit from anthracycline compared to non-anthracycline containing adjuvant breast cancer chemotherapy in some but not other studies. Chromosome 17 centromere (CEP17) duplication was measured on TMAs from formalin-fixed paraffin-embedded specimens obtained from 639 of 716 premenopausal women with node positive breast cancer who received cyclophosphamide, epirubicin and fluorouracil (CEF) or cyclophosphamide, methotrexate and fluorouracil (CMF) in the randomized controlled mammary 5 (MA.5) adjuvant trial. The prognostic impact of CEP17 duplication and its interactions with treatment were studied for relapse-free survival (RFS) and overall survival (OS). Overall, CEP17 duplication was not significantly associated with RFS or OS in multivariate analysis. For patients whose tumours had normal CEP17 copy number there were no apparent benefits for CEF compared to CMF for RFS (HR 0.98; 95% CI 0.68-1.42) or OS (HR 1.10; 95% CI 0.72-1.69). For patients whose tumours had CEP17 duplication, there was significant benefit for CEF compared to CMF for RFS (HR 0.54; CI 0.33-0.89) and a trend towards significance for OS (HR 0.64; CI 0.37-1.09). The adjusted P values for interaction between treatment and CEP17 duplication were 0.09 for RFS and 0.13 for OS. This study suggests that CEP17 duplication has a borderline association with clinical responsiveness to anthracycline containing chemotherapy similar to previous results seen with HER2 amplification and TOP2A alteration in MA.5. An appropriately powered meta-analysis is required to discriminate the predictive value of these three candidate markers.

Met induces mammary tumors with diverse histologies and is associated with poor outcome and human basal breast cancer.

Elevated MET receptor tyrosine kinase correlates with poor outcome in breast cancer, yet the reasons for this are poorly understood. We thus generated a transgenic mouse model targeting expression of an oncogenic Met receptor (Met(mt)) to the mammary epithelium. We show that Met(mt) induces mammary tumors with multiple phenotypes. These reflect tumor subtypes with gene expression and immunostaining profiles sharing similarities to human basal and luminal breast cancers. Within the basal subtype, Met(mt) induces tumors with signatures of WNT and epithelial to mesenchymal transition (EMT). Among human breast cancers, MET is primarily elevated in basal and ERBB2-positive subtypes with poor prognosis, and we show that MET, together with EMT marker, SNAIL, are highly predictive of poor prognosis in lymph node-negative patients. By generating a unique mouse model in which the Met receptor tyrosine kinase is expressed in the mammary epithelium, along with the examination of MET expression in human breast cancer, we have established a specific link between MET and basal breast cancer. This work identifies basal breast cancers and, additionally, poor-outcome breast cancers, as those that may benefit from anti-MET receptor therapies.

A role for the TGFbeta-Par6 polarity pathway in breast cancer progression.

The role of polarity signaling in cancer metastasis is ill defined. Using two three-dimensional culture models of mammary epithelial cells and an orthotopic mouse model of breast cancer, we reveal that Par6 signaling, which is regulated directly by TGFbeta, plays a role in breast cancer metastasis. Interference with Par6 signaling blocked TGFbeta-dependent loss of polarity in acini-like structures formed by non-transformed mammary cells grown in three-dimensional structures and suppressed the protrusive morphology of mesenchymal-like invasive mammary tumor cells without rescuing E-cadherin expression. Moreover, blockade of Par6 signaling in an in vivo orthotopic model of metastatic breast cancer induced the formation of ZO-1-positive epithelium-like structures in the primary tumor and suppressed metastasis to the lungs. Analysis of the pathway in tissue microarrays of human breast tumors further revealed that Par6 activation correlated with markers of the basal carcinoma subtype in BRCA1-associated tumors. These studies thus reveal a key role for polarity signaling and the control of morphologic transformation in breast cancer metastasis.

HER2 and TOP2A as predictive markers for anthracycline-containing chemotherapy regimens as adjuvant treatment of breast cancer: a meta-analysis of individual patient data.

BACKGROUND: Prediction of response to anthracycline-based therapy for breast cancer is challenging. We aimed to assess the value of HER2 and TOP2A as predictive markers of response to anthracycline-based adjuvant therapy in patients with early breast cancer. METHODS: We did a meta-analysis of individual patient data from five randomised adjuvant trials that compared anthracycline-based regimens with cyclophosphamide, methotrexate, and fluorouracil (CMF) regimens. We assessed the status of HER2 and TOP2A genes with fluorescent in-situ hybridisation. Tumour samples were submitted to an external laboratory for validation. We calculated hazard ratios (HR) to compare event-free survival (EFS) and overall survival in patients receiving anthracycline-based treatment with those receiving CMF in two HER2 cohorts (HER2 amplified and non-amplified tumours) and in three TOP2A cohorts (normal, amplified, and deleted tumours). FINDINGS: We analysed data for 3452 patients for HER2 and 3102 patients for TOP2A. For EFS, HRs were 0·89 (95% CI 0·79-1·01) for HER2 non-amplified patients and 0·71 (0·58-0·86) for HER2-amplified patients (p(interaction)=0·0485); for overall survival, HRs were 0·91 (95% CI 0·79-1·05) for HER2 non-amplified patients and 0·73 (0·59-0·89) for HER2-amplified patients (p(interaction)=0·0718). In analysis of TOP2A status, HRs for EFS were 0·88 (0·78-1·00) for normal, 0·63 (0·46-0·87) for deleted, and 0·62 (0·43-0·90) for amplified (p(interaction)=0·0513); HRs for overall survival were 0·89 (0·78-1·03) for normal, 0·68 (0·49-0·95) for deleted, and 0·67 (0·46-0·98) for amplified (p(interaction)=0·1608). When patients with TOP2A-deleted and TOP2A-amplified tumours were grouped together (altered cohort) and compared with data from patients with normal TOP2A tumours, HRs for EFS were 0·64 (0·50-0·81) for altered and 0·88 (0·78-1·00) for normal (p(interaction)=0·0183); HRs for overall survival were 0·67 (0·52-0·86) for altered and 0·89 (0·78-1·03) for normal (p(interaction)=0·0455). INTERPRETATION: Although HER2 amplification and combined TOP2A amplification and deletion may have some value in the prediction of responsiveness to anthracycline-based chemotherapy, our findings do not support the use of anthracyclines only in patients with HER2-amplified or TOP2A-aberrated tumours. FUNDING: Associazione Italiana Ricerca Cancro, Academy of Finland, Belgian Federation Against Cancer, Cancer Research UK, Les Amis de l'Institut Bordet, Scottish Breast Cancer Trials Group, NCIC Clinical Trials Group, Canadian Cancer Society Research Institute, Danish Council for Strategic Research, Pharmacia-Upjohn (now Pfizer), and Abbott Laboratories.

Contribution of large genomic BRCA1 alterations to early-onset breast cancer selected for family history and tumour morphology: a report from The Breast Cancer Family Registry.

INTRODUCTION: Selecting women affected with breast cancer who are most likely to carry a germline mutation in BRCA1 and applying the most appropriate test methodology remains challenging for cancer genetics services. We sought to test the value of selecting women for BRCA1 mutation testing on the basis of family history and/or breast tumour morphology criteria as well as the value of testing for large genomic alterations in BRCA1. METHODS: We studied women participating in the Breast Cancer Family Registry (BCFR), recruited via population-based sampling, who had been diagnosed with breast cancer before the age of 40 years who had a strong family history of breast or ovarian cancer (n = 187) and/or a first primary breast tumour with morphological features consistent with carrying a BRCA1 germline mutation (n = 133; 37 met both criteria). An additional 184 women diagnosed before the age of 40 years who had a strong family history of breast or ovarian cancer and who were not known to carry a germline BRCA1 mutation were selected from among women who had been recruited into the BCFR from clinical genetics services. These 467 women had been screened for BRCA1 germline mutations, and we expanded this testing to include a screen for large genomic BRCA1 alterations using Multiplex Ligation-dependent Probe Amplification. RESULTS: Twelve large genomic BRCA1 alterations were identified, including 10 (4%) of the 283 women selected from among the population-based sample. In total, 18 (12%), 18 (19%) and 16 (43%) BRCA1 mutations were identified in the population-based groups selected on the basis of family history only (n = 150), the group selected on the basis of tumour morphology only (n = 96) and meeting both criteria (n = 37), respectively. CONCLUSIONS: Large genomic alterations accounted for 19% of all BRCA1 mutations identified. This study emphasises the value of combining information about family history, age at diagnosis and tumour morphology when selecting women for germline BRCA1 mutation testing as well as including a screen for large genomic alterations.

EMSY and CCND1 amplification in familial breast cancer: from the Ontario site of the Breast Cancer Family Registry.

EMSY is a putative oncogene amplified in a minority of breast carcinomas, its protein product interacts with and transcriptionally silences BRCA2. We hypothesized that breast tumors from BRCA2 mutation carriers would be less likely than other familial breast cancers to exhibit EMSY amplification. As EMSY is located on 11q13 in proximity to CCND1, an established breast cancer oncogene, we also examined the amplification of CCND1 in the same tumor cohort. Amplification of EMSY and CCND1 were examined in 58 BRCA1-associated, 64 BRCA2-associated, and 242 familial non-BRCA1/BRCA2 breast cancers using fluorescent in situ hybridization (FISH). All tumors had a centralized pathology review and underwent molecular phenotyping by immunohistochemical profiling on tissue microarrays (TMAs). Tumors with amplification of EMSY and/or CCND1 were compared with non-amplified tumors for morphological appearance, molecular subtype, and overall survival. EMSY amplification was detected in 8% of BRCA1-associated, 0% of BRCA2-associated, and 9% of familial non-BRCA1/BRCA2 breast tumors (P = 0.036). CCND1 was amplified in 4% of BRCA1-associated, 13% of BRCA2-associated and 21% of non-BRCA1/BRCA2 breast tumors (P = 0.054). EMSY was amplified independently of CCND1 in 38% of cases. EMSY amplification was associated with increased tumor stage only; whereas CCND1 amplification was associated with high tumor grade, ER positivity, and inversely associated with the basal-like phenotype. There was a trend toward worse overall survival in ER-positive non-BRCA1/BRCA2 familial breast cancer patients whose tumors exhibited EMSY and CCND1 co-amplification. BRCA2-associated breast tumors are less likely than non-BRCA1/BRCA2 familial breast cancers to exhibit EMSY amplification. BRCA1-associated breast cancers are less likely than non-BRCA1/BRCA2 familial breast cancers to exhibit CCND1 amplification. EMSY amplification does occur independently of CCND1 amplification in a minority of familial breast cancers, supporting its role as a possible breast cancer oncogene.

Lobular neoplasia: morphology, biological potential and management in core biopsies.

Lobular neoplasia has been traditionally recognized as a marker of increased risk for subsequent breast carcinoma development; however, molecular studies suggest that it also behaves in a non-obligate precursor manner. We do not know, as yet, how to identify the subgroup of cases that is most likely to progress, but the epidemiological data would indicate that this progression occurs after a long period of time. Thus, the current approach of conservative management of these lesions when identified in excision specimens is justified. Recently, several variants of lobular carcinoma in situ (LCIS), most notably pleomorphic LCIS, have been recognized and these can be difficult to differentiate from ductal carcinoma in situ. Application of strict diagnostic criteria and the judicial use of immunohistochemistry, particularly E-cadherin, can be helpful in this differential diagnosis. Another challenging issue is the management of lobular neoplasia when diagnosed on core biopsy. This controversial issue will be discussed in detail. The goals of this review are (1) to describe the morphological criteria used to diagnose the spectrum of lobular neoplastic lesions, including atypical lobular hyperplasia, LCIS and variants of LCIS; (2) to discuss the data exploring the biological potential of lobular neoplasia from an epidemiological and molecular viewpoint; and (3) to outline the recommendations for management of lobular neoplasia when encountered in core biopsies.

HER2 and responsiveness of breast cancer to adjuvant chemotherapy.

BACKGROUND: Amplification of the human epidermal growth factor receptor type 2 (HER2, also called HER2/neu) gene and overexpression of its product in breast-cancer cells may be associated with responsiveness to anthracycline-containing chemotherapy regimens. METHODS: In the randomized, controlled Mammary.5 trial, we studied 639 formalin-fixed paraffin-embedded specimens obtained from 710 premenopausal women with node-positive breast cancer who had received either cyclophosphamide, epirubicin, and fluorouracil (CEF) or cyclophosphamide, methotrexate, and fluorouracil (CMF) as adjuvant chemotherapy. HER2 amplification or overexpression was evaluated with the use of fluorescence in situ hybridization, immunohistochemical analysis, and polymerase-chain-reaction analysis. RESULTS: Amplification of HER2 was associated with a poor prognosis regardless of the type of treatment. In patients whose tumors showed amplification of HER2, CEF was superior to CMF when assessed on the basis of relapse-free survival (hazard ratio, 0.52; 95 percent confidence interval, 0.34 to 0.80; P=0.003) and overall survival (hazard ratio, 0.65; 95 percent confidence interval, 0.42 to 1.02; P=0.06). For women whose tumors lacked amplification of HER2, CEF did not improve relapse-free survival (hazard ratio for relapse, 0.91; 95 percent confidence interval, 0.71 to 1.18; P=0.49) or overall survival (hazard ratio for death, 1.06; 95 percent confidence interval, 0.83 to 1.44; P=0.68). The adjusted hazard ratio for the interaction between treatment and HER2 amplification was 1.96 for relapse-free survival (95 percent confidence interval, 1.15 to 3.36; P=0.01) and 2.04 for overall survival (95 percent confidence interval, 1.14 to 3.65; P=0.02). CONCLUSIONS: Amplification of HER2 in breast-cancer cells is associated with clinical responsiveness to anthracycline-containing chemotherapy. (cancer.gov number, NCI-V90-0027.).

Expression profiling of familial breast cancers demonstrates higher expression of FGFR2 in BRCA2-associated tumors.

BACKGROUND: BRCA1- and BRCA2-associated tumors appear to have distinct molecular signatures. BRCA1-associated tumors are predominantly basal-like cancers, whereas BRCA2-associated tumors have a predominant luminal-like phenotype. These two molecular signatures reflect in part the two cell types found in the terminal duct lobular unit of the breast. To elucidate novel genes involved in these two spectra of breast tumorigenesis we performed global gene expression analysis on breast tumors from germline BRCA1 and BRCA2 mutation carriers. METHODOLOGY: Breast tumor RNAs from 7 BRCA1 and 6 BRCA2 mutation carriers were profiled using UHN human 19K cDNA microarrays. Supervised univariate analyses were conducted to identify genes differentially expressed between BRCA1 and BRCA2-associated tumors. Selected discriminatory genes were validated using real time reverse transcription polymerase chain reaction in the tumor RNAs, and/or by immunohistochemistry (IHC) or by in situ hybridization (ISH) on tissue microarrays (TMAs) containing an independent set of 58 BRCA1 and 64 BRCA2-associated tumors. RESULTS: Genes more highly expressed in BRCA1-associated tumors included stathmin, osteopontin, TGFbeta2 and Jagged 1 in addition to genes previously identified as characteristic of basal-like breast cancers. BRCA2-associated cancers were characterized by the higher relative expression of FGF1 and FGFR2. FGFR2 protein was also more highly expressed in BRCA2-associated cancers (P = 0.004). SIGNIFICANCE: BRCA1-associated tumours demonstrated increased expression of component genes of the Notch and TGFbeta pathways whereas the higher expression of FGFR2 and FGF1 in BRCA2-associated cancers suggests the existence of an autocrine stimulatory loop.

Family history of breast cancer and all-cause mortality after breast cancer diagnosis in the Breast Cancer Family Registry.

Although having a family history of breast cancer is a well established breast cancer risk factor, it is not known whether it influences mortality after breast cancer diagnosis. We studied 4,153 women with first primary incident invasive breast cancer diagnosed between 1991 and 2000, and enrolled in the Breast Cancer Family Registry through population-based sampling in Northern California, USA; Ontario, Canada; and Melbourne and Sydney, Australia. Cases were oversampled for younger age at diagnosis and/or family history of breast cancer. Carriers of germline mutations in BRCA1 or BRCA2 were excluded. Cases and their relatives completed structured questionnaires assessing breast cancer risk factors and family history of cancer. Cases were followed for a median of 6.5 years, during which 725 deaths occurred. Cox proportional hazards regression was used to evaluate associations between family history of breast cancer at the time of diagnosis and risk of all-cause mortality after breast cancer diagnosis, adjusting for established prognostic factors. The hazard ratios for all-cause mortality were 0.98 (95% confidence interval [CI] = 0.84-1.15) for having at least one first- or second-degree relative with breast cancer, and 0.85 (95% CI = 0.70-1.02) for having at least one first-degree relative with breast cancer, compared with having no such family history. Estimates did not vary appreciably when stratified by case or tumor characteristics. In conclusion, family history of breast cancer is not associated with all-cause mortality after breast cancer diagnosis for women without a known germline mutation in BRCA1 or BRCA2. Therefore, clinical management should not depend on family history of breast cancer.

Changes in estrogen receptor, progesterone receptor and Her-2/neu status with time: discordance rates between primary and metastatic breast cancer.

BACKGROUND: Changes in the receptor profile between primary and metastatic breast cancer tissue have been suggested. The degree of hormone receptor discordance in archival paired pathological samples was evaluated. MATERIALS AND METHODS: Archival data were collected on 100 patients for whom tissue from primary and metastatic sites was available. Estrogen receptor (ER), progesterone receptor (PR) and Her-2/neu status in the primary and metastasis were compared. RESULTS: The discordance rate for ER was 17.7% (2-sided p=0.0039) with 9.7% of tumours changing from ER-positive to ER-negative and 8.0% changing from ER-negative to ER-positive. The discordance rate for PR was 37.3% (2-sided p<0.0001), with all of these tumours changing from PR-positive to PR-negative. No significant discordance for Her-2/neu was found. CONCLUSIONS: This series suggests that significant discordance exists for hormone receptor status between primary and metastatic breast cancer samples. Loss of PR was particularly frequent.

Prognostic effect of basal-like breast cancers is time dependent: evidence from tissue microarray studies on a lymph node-negative cohort.

PURPOSE: To determine whether data obtained from tissue microarrays (TMA) of a prospectively accrued node-negative breast cancer cohort are prognostically informative, we compared data derived from TMA with previously determined molecular markers. Subsequent to this validation, we examined outcome in specific subgroups defined using TMA data. EXPERIMENTAL DESIGN: A consecutive series of 1,561 patients were followed for recurrence (median follow-up of 107 months). Estrogen receptor, progesterone receptor, p53, and HER2 expression, examined using TMA constructed from 887 tumors, was compared with status evaluated previously by biochemical and molecular methods. The associations with risk of recurrence were examined for biomarkers as well as for HER2, luminal, and basal subgroups defined by immunohistochemical expression. RESULTS: In line with earlier molecular studies, a significant risk of recurrence was found in patients with HER2 overexpression (relative risk = 2.30; P = 0.002) and p53-positive tumors (relative risk = 1.81; P = 0.005) in univariate Cox model analysis. Although complete concordance between methodologies was not observed for estrogen receptor and progesterone receptor, their associations with disease-free survival were consistent with established prognostic findings. Patients with basal-type tumors fared worse within 36 months of diagnosis but not thereafter. CONCLUSIONS: This study shows the clinical validity of TMA in evaluating the importance of prognostic markers in this cohort. Furthermore, it shows a marked time-dependent effect in tumor subgroups, most notable within the basal subgroup. Our data suggest that patients with basal-like tumors may be broadly separable into two clinically distinctive groups: those likely to experience disease recurrence in the short term and those that will experience long-term survival.

Comparison of wait times across the breast cancer treatment pathway among screened women undergoing organized breast assessment versus usual care.

OBJECTIVE: The benefit of organized breast assessment on wait times to treatment among asymptomatic women is unknown. The Ontario Breast Screening Program (OBSP) offers screening and organized assessment through Breast Assessment Centres (BAC). This study compares wait times across the treatment pathway among screened women diagnosed with breast cancer through BAC and usual care (UC). METHODS: A retrospective design identified two concurrent cohorts of postmenopausal women aged 50-69 within the OBSP diagnosed with screen-detected invasive breast cancer and assessed in BAC (n = 2010) and UC (n = 1844) between 2002 and 2010. Demographic characteristics were obtained from the OBSP. Medical chart abstraction provided prognostic and treatment data. Multinomial logistic regression examined associations of assessment type with wait times from abnormal mammogram to surgery, chemotherapy or radiotherapy. RESULTS: Compared with through UC, postmenopausal women diagnosed through BAC were significantly less likely to have longer wait times (days) from an abnormal mammogram to definitive surgery (> 89 vs. ≤ 47; OR = 0.63; 95% CI = 0.52-0.77), from final surgery to radiotherapy (> 88 vs. ≤ 55; OR = 0.71; 95% CI = 0.54-0.93) and from final chemotherapy to radiotherapy (> 41 vs. ≤ 28; OR = 0.52; 95% CI = 0.36-0.76). Conversely, women assessed through BAC compared with through UC were more likely to experience longer wait times from final surgery to chemotherapy (> 64 vs. ≤ 40; OR = 1.49; 95% CI = 1.04-2.14). CONCLUSION: Shorter wait times to most treatments for postmenopausal women diagnosed in BAC further supports that women with an abnormal mammogram should be managed through organized assessment. Continued evaluation of factors influencing wait times to treatment is essential for quality improvement and patient outcomes.