Genomic differences between pure ductal carcinoma in situ and synchronous ductal carcinoma in situ with invasive breast cancer

Although ductal carcinoma in situ (DCIS) precedes invasive ductal carcinoma (IDC), the related genomic alterations remain unknown. To identify the genomic landscape of DCIS and better understand the mechanisms behind progression to IDC, we performed whole-exome sequencing and copy number profiling for six cases of pure DCIS and five pairs of synchronous DCIS and IDC. Pure DCIS harbored well-known mutations (e.g., TP53, PIK3CA and AKT1), copy number alterations (CNAs) and chromothripses, but had significantly fewer driver genes and co-occurrence of mutation/CNAs than synchronous DCIS-IDC. We found neither recurrent nor significantly mutated genes with synchronous DCIS-IDC compared to pure DCIS, indicating that there may not be a single determinant for pure DCIS progression to IDC. Of note, synchronous DCIS genomes were closer to IDC than pure DCIS. Among the clinicopathologic parameters, progesterone receptor (PR)-negative status was associated with increased mutations, CNAs, co-occurrence of mutations/CNAs and driver mutations. Our results indicate that although pure DCIS has already acquired some drivers, more changes are needed to progress to IDC. In addition, IDC-associated DCIS is more aggressive than pure DCIS at genomic level and should really be considered IDC. Finally, the data suggest that PR-negativity could be used to predict aggressive breast cancer genotypes.     

Vascular density and phenotype around ductal carcinoma in situ (DCIS) of the breast

Up to 50% of recurrences of ductal carcinoma in situ of the breast are associated with invasive carcinoma but no pathological or molecular features have yet been found to predict for the development of invasive disease. For a tumour to invade, it requires the formation of new blood vessels. Previous studies have described a vascular rim around ducts involved by ductal carcinoma in situ, raising the possibility that the characteristics of periductal vascularisation may be important in determining transformation from in situ to invasive disease. Periductal vascular density and phenotype were determined using morphometry and a panel of anti-endothelial antibodies (von Willebrand factor, CD31, CD141 and CD34) and related to the presence of invasive carcinoma and other histological features. Compared to normal lobules, pure ductal carcinoma in situ exhibited a greater density of CD34+ and CD31+ vessels but a decrease in those that were immunopositive for vWF, indicating a difference in phenotype and in density. Ductal carcinoma in situ associated with invasive carcinoma showed a profile of vascular immunostaining similar to that of pure ductal carcinoma in situ but there were significantly greater numbers of CD34+ and CD141+ vessels and fewer staining for vWF. There was a significant negative correlation between vascular density and both the cross-sectional areas of the ducts involved and the extent of the necrosis of the tumour they contained. A correlation between vascular density and nuclear grade was also noted, being highest in the intermediate grade. The greater density of CD34+ and CD141+ vessels around ductal carcinoma in situ associated with invasive carcinoma could reflect a greater predisposition to invade but a direct effect of co-existent invasive carcinoma cannot entirely be ruled out in the present study. The relationship between vascular density, grade, duct size and nuclear grade suggests that periductal angiogenesis increases with tumour growth rate but is unable to keep pace with the most rapidly growing lesions.     

Immunohistochemical categorisation of ductal carcinoma in situ of the breast

The aim of this study is to analyse whether immunohistochemistry (IHC) applying a broad set of markers could be used to categorise ductal carcinoma in situ (DCIS) of the breast in distinct subgroups corresponding to the recently defined molecular categories of invasive carcinoma. Immunohistochemistry of pure DCIS cases constructed in tissue arrays was performed with 16 markers (oestrogen receptor (ER), progesterone receptor (PR), androgen receptor (AR), Bcl-2, p53, Her2, insulin-like growth factor receptor, E-cadherin, epithelial membrane antigen (EMA), CA125, keratins 5/6, 14, 19, epidermal growth factor receptor, S100, and CD31). Results in 163 cases were analysed by unsupervised hierarchical clustering. Histological classification was performed by review of whole tissue sections and identified 36 well-, 55 intermediately, and 72 poorly differentiated DCISs. Unsupervised hierarchical cluster analysis categorised DCIS into two major groups that could be further subdivided into subgroups based on the expression of six markers (ER, PR, AR, Bcl-2, p53, and Her2). In the major predominantly ER/Bcl-2-positive (luminal) group, three subgroups (AR-positive (n=33), AR-negative (n=40), and mixed (n=34)) could be identified and included 34 well-differentiated DCISs. Within the major predominantly ER/Bcl-2-negative (nonluminal) group, a Her2-positive subgroup (n=34) was characterised by 31 poorly differentiated lesions. Eight triple-negative lesions, including one positive for keratin 5/6 and two positive for p53, were encountered. Intermediately differentiated DCIS shared a comparable IHC staining pattern with well-differentiated DCIS that was distinct from poorly differentiated DCIS (P<0.001). Ductal carcinoma in situ could be categorised by IHC into two major groups and five subgroups using six markers. Morphologically, intermediately differentiated DCIS seems to have more biological similarities with well-differentiated lesions as compared to poorly differentiated lesions.     

Grade of recurrent in situ and invasive carcinoma following treatment of pure ductal carcinoma in situ of the breast

The grade of recurrent in situ and invasive carcinoma occurring after treatment of pure ductal carcinoma in situ (DCIS) has been compared with the grade of the original DCIS in 122 patients from four different centres (The Royal Marsden Hospitals, London and Sutton, 57 patients; Guy's Hospital, London, 19 patients; Nottingham City Hospital, 31 patients and The Royal Liverpool Hospital, 15 patients). The recurrent carcinoma was pure DCIS in 70 women (57%) and in 52 women (43%) invasive carcinoma was present, which was associated with an in situ element in 43. In all, 19 patients developed a second recurrence (pure DCIS in 11 and invasive with or without an in situ element in eight). The majority of invasive carcinomas followed high-grade DCIS. There was strong agreement between the grade of the original DCIS and that of the recurrent DCIS (kappa=0.679), which was the same in 95 of 113 patients (84%). The grade of the original DCIS showed only fair agreement with the grade of recurrent invasive carcinoma (kappa=0.241), although agreement was stronger with the pleomorphism score of the recurrent carcinoma (kappa=0.396). There was moderate agreement, in recurrent invasive lesions, between the grade of the DCIS and that of the associated invasive element (kappa=0.515). Other features that showed moderate or strong agreement between the original and recurrent DCIS were necrosis and periductal inflammation. The similarity between the histological findings of the original and subsequent DCIS is consistent with the concept that recurrent lesions represent regrowth of residual carcinoma. In addition, although agreement between the grade of the original DCIS and that of any subsequent invasive carcinoma was only fair, there is no suggestion that low-grade DCIS lesions progress to higher grade lesions or to the development of higher grade invasive carcinoma. This is in agreement with immunohistochemical and molecular data indicating that low-grade and high-grade mammary carcinomas are quite different lesions.     

The effect of DCIS grade on rate, type and time to recurrence after 15 years of follow-up of screen-detected DCIS

Background:

The incidence of ductal carcinoma in situ (DCIS) rose rapidly when the NHS Breast Screening Programme (NHSBSP) started in 1988. Some authorities consider that this represents both over-diagnosis and over-treatment. We report long-term follow-up of DCIS diagnosed in the first 10 years (April 1988 to March 1999) of the West Midlands NHSBSP.

Methods:

840 noninvasive breast cancers were recorded on the national breast screening computer system. Following exclusions, and thorough case note and pathology review, 700 DCIS cases were identified for follow-up.

Results:

After a median follow-up of 183 (range 133 to 259) months, 102 (14.6%) first local recurrences were identified, 49 (48%) were invasive. Median time to first noninvasive recurrence was 15 months, and 60 months for invasive recurrence. Median time to invasive recurrence was 76 months from initially high-grade DCIS, and 131 months from low/intermediate grade DCIS. For the seven women, presenting with metastasis as their first event, the median time was 82 (range 15 to 188) months. The cumulative proportion developing recurrence at 180 months was twice as high as at 60 months.

Interpretation:

Short-term follow-up of patients diagnosed with DCIS will miss significant numbers of events, especially invasive local recurrences.     

Ductal carcinoma in situ in a 25-year-old man presenting with apparent unilateral gynecomastia

Ductal carcinoma in situ (dcis) in a young man is rarely reported. Our patient, a 25-year-old man, presented with apparent symptomatic unilateral gynecomastia. He has a strong history of cancer on both the maternal and paternal sides of his family, including breast and lung (maternal) and melanoma, colon, and pancreatic (paternal). His mother tested negative for BRCA1 and BRCA2. There is no information on paternal genetic testing.The patient was treated with left subcutaneous mastectomy. Upon histologic review of the sample, concurrent gynecomastia and dcis were discovered. To date, only 4 cases of gynecomastia and dcis have been described in younger male patients. Because only 30%–50% of patients with dcis eventually develop invasive cancer in the subsequent 10–20 years, dcis prevalence in the general population may be higher than predicted. This case underscores the importance of family history in any patient presenting with a breast mass. Patients must be made aware of the risk, however small it may be, and physicians must remain cautious of cancer in young men with gynecomastia.     

Expression patterns of angiogenic and lymphangiogenic factors in ductal breast carcinoma in situ

The objective of this study was to investigate expression of various growth factors associated with angiogenesis and lymphangiogenesis and of their receptors in ductal carcinomas in situ of the breast (DCIS). We studied protein expression of basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF)-A, endothelin (ET)-1, and VEGF-C, and their receptors bFGF-R1, Flt-1, KDR, ET(A)R, ET(B)R, and Flt-4 immunohistochemically in 200 DCIS (pure DCIS: n=96; DCIS adjacent to an invasive component: n=104) using self-constructed tissue microarrays. Basic fibroblast growth factor-R1, VEGF-C, Flt-4, and ET(A)R were expressed in the tumour cells in the majority of cases, whereas bFGF and Flt-1 expression was rarely observed. VEGF-A, KDR, ET-1, and ET(B)R were variably expressed. The findings of VEGF-C and its receptor Flt-4 as lymphangiogenic factors being expressed in tumour cells of nearly all DCIS lesions and the observed expression of various angiogenic growth factors in most DCIS suggest that in situ carcinomas are capable of inducing angiogenesis and lymphangiogenesis. Moreover, we found a higher angiogenic activity in pure DCIS as compared to DCIS with concomitant invasive carcinoma. This association of angiogenic factors with pure DCIS was considerably more pronounced in the subgroup of non-high-grade DCIS (n=103) as compared with high-grade DCIS (n=94). Determination of these angiogenic markers may therefore facilitate discrimination between biologically different subgroups of DCIS and could help to identify a particularly angiogenic subset with a potentially higher probability of recurrence or of progression to invasiveness. For these DCIS, targeting angiogenesis may represent a feasible therapeutic approach for prevention of progression of DCIS to invasion.     

Nipple aspirate fluid color is associated with breast cancer

BACKGROUND: Fluid can be non-invasively aspirated from the breast nipple (nipple aspirate fluid, NAF). NAF may have many colors, including clear, white, yellow, green, and red/brown. While bloody spontaneous nipple discharge has been linked with breast cancer, the association of NAF color with cancer is not established. Our hypothesis was that red/brown NAF color was associated with breast cancer. The purpose of this study was to assess (1) if red/brown NAF is associated with the presence and progression of breast cancer, (2) the influence of prior needle or surgical biopsy on NAF color, and (3) if an association between NAF color and breast cancer was found, to develop a cancer predictive model including NAF color and cytology, and clinical information. METHODS: Specimens were obtained from 848 breasts between 1999 and 2004 after subjects enrolled in an IRB approved protocol to evaluate biologic markers of breast cancer. Cytologic evaluation was performed on Papanicolaou-stained cytospin preparations of NAF. RESULTS: Red/brown NAF was associated with breast cancer when considering all samples (p<0.001) and samples from women who did not undergo recent surgery (p=0.005). Needle biopsy did not, but surgical biopsy did influence NAF color. For the 327 women with NAF collected from both breasts, there was a significant association between red/brown NAF color and the presence of breast cancer (p=0.005). Red/brown NAF was more common in breasts with ductal carcinoma in situ than atypical hyperplasia (p=0.008). The optimal model, included NAF color, cytology, and age, was 92% sensitive and 61% specific in predicting if a woman had breast cancer. CONCLUSIONS: NAF color was associated with the presence of breast cancer and the progression from precancer to cancer in a population of women who presented to a breast cancer evaluation clinic. NAF color contributed to a highly predictive breast cancer detection model. Additional studies are warranted to determine the usefulness of NAF color in the assessment of women who present for breast cancer evaluation.     

Increased risk of second malignancies after in situ breast carcinoma in a population-based registry

Among 1276 primary breast carcinoma in situ (BCIS) patients diagnosed in 1972-2002 in the Southern Netherlands, 11% developed a second cancer. Breast carcinoma in situ patients exhibited a two-fold increased risk of second cancer (standardised incidence ratios (SIR): 2.1, 95% confidence interval (CI): 1.7-2.5). The risk was highest for a second breast cancer (SIR: 3.4, 95% CI: 2.6-4.3; AER: 66 patients per 10,000 per year) followed by skin cancer (SIR: 1.7, 95% CI: 1.1-2.6; AER: 17 patients per 10,000 per year). The increased risk of second breast cancer was similar for the ipsilateral (SIR: 1.9, 95% CI: 1.3-2.7) and contralateral (SIR: 2.0, 95% CI: 1.4-2.8) breast. Risk of second cancer was independent of age at diagnosis, type of initial therapy, histologic type of BCIS and period of diagnosis. Standardised incidence ratios of second cancer after BCIS (SIR: 2.3, 95% CI: 1.8-2.8) resembled that after invasive breast cancer (SIR: 2.2, 95% CI: 2.1-2.4). Surveillance should be directed towards second (ipsi- and contra-lateral) breast cancer.     

Incidence and possible pathogenesis of sentinel node micrometastases in ductal carcinoma in situ of the breast detected using molecular whole lymph node assay

Background:

The pathogenesis of lymph node metastases in preinvasive breast cancer – ductal carcinoma in situ (DCIS) – remains controversial. The one-step nucleic acid amplification (OSNA) assay is a novel molecular method that can assess a whole node and detect clinically relevant metastases. In this retrospective cohort study, we determined the performance of the OSNA assay in DCIS and the pathogenesis of node-positive DCIS.

Methods:

The subjects consisted of 623 patients with DCIS who underwent sentinel lymph node (SN) biopsy. Of these, 2-mm-sectioned nodes were examined using frozen-section (FS) histology in 338 patients between 2007 and 2009, while 285 underwent OSNA whole node assays between 2009 and 2011. The SN-positivity rate was compared between cohorts, and the characteristics of OSNA-positive DCIS were investigated.

Results:

The OSNA detected more cases of SN metastases than FS histology (12 out of 285, 4.2% vs 1 out of 338, 0.3%). Most of the metastases were micrometastases. The characteristics of high-risk DCIS (i.e., mass formation, size, grade, and comedo) and preoperative breast biopsy (i.e., methods or time to surgery) were not valid for OSNA assay–positive DCIS.

Conclusion:

The OSNA detects more SN metastases in DCIS than FS histology. Further examination of the primary tumours and follow-up of node-positive DCIS are needed to elucidate the pathogenesis.     

Risk of subsequent invasive breast carcinoma after in situ breast carcinoma in a population covered by national mammographic screening

Sweden was the first country to establish a nationwide breast cancer screening service. We used the Swedish Family-Cancer Database to evaluate the risk of invasive carcinoma after in situ carcinoma of the breast. Risk estimates for contralateral and ipsilateral invasive malignancies following age and histology specific in situ breast carcinomas were calculated using Poisson's regression analysis. The agreement between concordant and discordant morphologies of invasive and in situ breast cancer was measured using the kappa statistic. Women with in situ breast cancer showed a relative risk of 2.03 for contralateral and 3.94 for ipsilateral invasive breast cancer. The risk was higher for in situ carcinomas diagnosed before the age of 50 years and after lobular in situ breast cancers. A comparison of the risks during the past decades suggested that the risk of ipsilateral breast cancer has increased in Sweden but that of contralateral breast cancer has remained unchanged. In situ and the subsequent invasive breast cancers did not seem to share their morphologies.     

Pathological complete response and residual DCIS following neoadjuvant chemotherapy for breast carcinoma

Patients who have no residual invasive cancer following neoadjuvant chemotherapy for breast carcinoma have a better overall survival than those with residual disease. Many classification systems assessing pathological response to neoadjuvant chemotherapy include residual ductal carcinoma in situ (DCIS) only in the definition of pathological complete response. The purpose of this study was to investigate whether patients with residual DCIS only have the same prognosis as those with no residual invasive or in situ disease. A retrospective analysis of a prospectively maintained database identified 435 patients, who received neoadjuvant chemotherapy for operable breast cancer between February 1985 and February 2003. Of these, 30 (7%; 95% CI 5-9%) had no residual invasive disease or DCIS and 20 (5%; CI 3-7%) had residual DCIS only. With a median follow-up of 61 months, there was no statistical difference in disease-free survival, 80% (95% CI 60-90%) in those with no residual invasive or in situ disease and 61% (95% CI 35-80%) in those with DCIS only (P=0.4). No significant difference in 5-year overall survival was observed, 93% (95% CI 75-98%) in those with no residual invasive or in situ disease and 82% (95% CI 52-94%) in those with DCIS only (P=0.3). Due to the small number of patients and limited number of events in each group, it is not possible to draw definitive conclusions from this study. Further analyses of other databases are required to confirm our finding of no difference in disease-free and overall survival between patients with residual DCIS and those with no invasive or in situ disease following neoadjuvant chemotherapy for breast cancer.     

The occurrence of invasive cancers following a diagnosis of breast carcinoma in situ

Approximately 1 in every 600 women attending breast-screening programmes in the United Kingdom is diagnosed with breast carcinoma in situ (BCIS). However, there is little information on the occurrence of subsequent cancers (other than second breast cancers) in these women. We investigated the occurrence of invasive cancers in 12,836 women diagnosed with BCIS in southeast England between 1971 and 2003, using data from the Thames Cancer Registry. A greater than expected number of subsequent cancers was found for two sites: breast (standardised incidence ratio (SIR) 1.96; 95% confidence interval (CI) 1.79-2.14) and corpus uteri (SIR 1.42; 95% CI 1.11-1.78). For subsequent ipsilateral breast cancer in those treated with breast conservation, the excess was independent of the time since diagnosis of BCIS, whereas for subsequent contralateral breast cancer, there was a steady decline in excess over time. For subsequent uterine cancer, the excess became statistically significant only at >5 years after BCIS diagnosis, consistent with a treatment effect. This was further supported by Cox regression analysis: the risk of subsequent uterine cancer was significantly increased in women receiving hormonal therapy compared with those not receiving it, with a hazard ratio of 2.97 (95% CI 1.84-4.80).     

Semi-quantitative immunohistochemical analysis of aromatase expression in ductal carcinoma in situ of the breast

Although estrogens whose production is catalyzed by aromatase are considered to play a role in human breast carcinogenesis, it remains unclear whether aromatase expression occurs in ductal carcinoma in situ (DCIS) of the breast. Aromatase expression in 61 cases of pure DCIS and 101 cases of invasive ductal carcinoma (IDC) was investigated by immunohistochemical analysis using a polyclonal anti-aromatase antibody. The level of aromatase expression was semiquantified by the H-score which was estimated by the percentage of positive-staining cells and the intensity of staining. The levels of aromatase expression were compared between the DCIS and IDC samples, and were also compared among the tumor cells and stromal cells in the DCIS and IDC samples. Positive cytoplasmic staining for aromatase expression was found not only in stromal cells but also in tumor cells. The levels of aromatase expression in the tumor cells and stromal cells from the DCIS samples were significantly higher than those in the respective cells from the IDC samples. Among the DCIS samples, those specimens from patients of ages 50 years or over showed higher levels of aromatase expression in stromal cells, than those from patients below 50 years. The finding that significantly higher aromatase expression levels were found in DCIS than in IDC indicates that it may be possible to treat DCIS patients with aromatase inhibitors, especially as an adjuvant hormonal therapy for postmenopausal patients.     

Preclinical mouse models for BRCA1-associated breast cancer

A substantial part of all hereditary breast cancer cases is caused by BRCA1 germline mutations. In this review, we will discuss the insights into BRCA1 functions that we obtained from mouse models with conventional and conditional mutations in Brca1. The most advanced models closely resemble human BRCA1-related breast cancer and may therefore be useful for addressing clinically relevant questions.     

A new pathological system for grading DCIS with improved prediction of local recurrence: results from the UKCCCR/ANZ DCIS trial

Background:

There is no consensus agreement regarding optimal management of locally excised ductal carcinoma in situ (DCIS) or features of greatest assistance in predicting disease behaviour. Cases in the UKCCCR/ANZ DCIS trial have been histologically reviewed to determine the features of prognostic importance.

Method:

A total of 72% of 1694 cases entered into the UKCCCR/ANZ DCIS trial had full pathological review. A large number of histological features were assessed, blinded to outcome and compared regarding ability to predict ipsilateral recurrence, as either DCIS or progression to invasive carcinoma.

Results:

Pathological features associated with ipsilateral recurrence in univariate analysis included high cytonuclear grade, larger lesion size, growth pattern, presence of necrosis or chronic inflammation, incompleteness (or uncertainty of completeness) of excision and smaller margin width. Receipt of post-operative radiotherapy was also a strong prognostic factor.We report a novel sub-division of the large group of high-grade lesions, which enables identification of a very poor prognosis sub-group; namely, DCIS that is of high cytonuclear grade, predominantly (>50%) solid architecture, bearing extensive comedo-type necrosis (>50% of ducts). In addition, we found little difference in ipsilateral recurrence rates between low- and intermediate-grade groups. Hazard ratios for low, intermediate, high and the new, very high, grade were 0.42, 0.33, 0.62 and 1.00, respectively, for ipsilateral in situ or invasive recurrence.

Conclusion:

We present a novel pathological classification for DCIS with substantially better prognostic discrimination for ipsilateral recurrence than the classical categorisation based on cytonuclear grade alone.     

Family history of breast and ovarian cancer and the risk of breast carcinoma in situ

A family history of breast cancer is an important risk factor for breast carcinoma in situ (BCIS), however, there are no detailed analyses of its variation in effect by number, type, laterality or age at onset of affected relatives nor by association with ovarian cancer. In addition, the role of the breast cancer susceptibility genes, BRCA1 and BRCA2, in the development of BCIS is unclear. Objective. To better define the role of: (1) a family history of breast and ovarian cancer and (2) the cancer susceptibility genes, BRCA1 and BRCA2, in the development of BCIS. Methods. The data are 875 ductal carcinoma in situ (DCIS) and 123 lobular carcinoma in situ (LCIS) cases diagnosed among residents of the state of Connecticut from September 15, 1994 to March 14, 1998 and between the age of 20 and 79 years. Controls (n = 999) are female Connecticut residents collected via random-digit-dial and frequency matched to the cases by 5-year age intervals. Telephone interviews were used to collect information on risk factors and cancer screening history.Logistic regression was used to provide maximum likelihood estimates of the odds ratios (OR) with 95% confidence intervals (95% CI). The probability of being a BRCA1 and/or BRCA2 gene carrier was calculated for each case and control, using family history of breast and ovarian cancer, age/age at diagnosis for relatives, prevalence and penetrance data for BRCA1/BRCA2, and self-report of Jewish heritage. Results. Cases with DCIS or LCIS were significantly more likely to report a first degree family history of breast cancer (OR: 1.6, 95% CI: 1.3, 2.1 and 1.8, 95% CI: 1.2, 2.9, respectively) than were controls. In addition, DCIS cases were 2.4 (95% CI: 0.8, 7.2) times more likely than controls to report both an affected mother and sister. An inverse association was suggested between age at onset and DCIS risk with cases aged 49 years or younger at 2.1 (95% CI: 1.3, 3.4) times the risk of controls (95% CI) versus 1.5 (95% CI: 1.1, 2.0) for cases older than 49 years. An elevated risk of DCIS was associated with a family history of ovarian cancer but did not reach statistical significance (OR: 1.3, 95% CI: 0.7, 2.5). Approximately 3.7% and 1.9% of DCIS cases were predicted to carry a mutation in BRCA1 and BRCA2, respectively. Conclusions. A family history of breast cancer is associated with an increased risk of DCIS and LCIS, particularly among women with multiple relatives affected at early ages. Statistical risk models predict a low prevalence rate of BRCA1 and BRCA2 in DCIS; these estimates await confirmation through laboratory testing.     

Chromosome instability and benefit from adjuvant anthracyclines in breast cancer

Background:

Duplication of the centromeric region of chromosome 17 (Ch17CEP) is associated with sensitivity to anthracyclines. An explanation may be chromosome instability (CIN); a frequent event in solid tumours associated with poor outcome. The predictive value of CIN seems to be drug dependent and CIN has been associated with both sensitivity and resistance to chemotherapy.

Methods:

In this study, we used fluorescent in situ hybridisation for chromosomes 1, 7, 11, 17 and 18 to identify patients with high tumour CIN% in 322 patients recruited into the BR9601 clinical trial.

Results:

High tumour CIN% was correlated to Ch17CEP (P=3.68e−7) and is associated with a reduced RFS (P=0.0011) and OS (P=0.04). Patients with high CIN had a decreased risk of death on E-CMF compared with CMF.

Conclusion:

CIN is of prognostic significance and may be of predictive value in determining anthracycline response, although further testing is required.