Primary Operable Breast Carcinoma Research Articles

Elastin and collagen IV double staining: A refined method to detect blood vessel invasion in breast cancer.

Blood vessel invasion (BVI) is a prognostic indicator in various cancers. Elastic stain, which highlights blood vessel walls, is commonly used to detect BVI. In the breast, however, its diagnostic usefulness is limited because it also highlights some intraductal carcinoma components, which often mimic BVI. In this study, we aimed to improve BVI detection in breast cancer and developed a double staining: Victoria blue for elastin and immunohistochemistry for collagen IV. Collagen IV fibers were retained along the basement membranes of intraductal carcinoma components, whereas they were rearranged or lost in BVI. From these observations, we defined BVI as the presence of tumor cells inside an elastic ring with a rearrangement or loss of collagen IV fibers. Using these criteria, we found BVI in 148 cases (49%) among 304 cases of primary operable invasive breast carcinoma, and the presence of BVI correlated significantly with poor prognosis. By contrast, we detected BVI in 94 cases (31%) or 14 cases (5%) by elastic van Gieson or CD31 immunostaining among the same cases, respectively, with no statistically significant association with prognosis. Thus, elastin and collagen IV double staining facilitates the detection of BVI in breast cancer and is useful to predict prognosis.

Utility of One-Step Nucleic Acid (OSNA) cytokeratin-19 amplification assay total tumour load (TTL) in survival prediction, in primary operable invasive breast carcinoma

Introduction: One-Step Nucleic acid Amplification (OSNA) can be used to quantitatively stage axillary node involvement in patients with breast carcinoma. Recently, OSNA total CK19mRNA copy number (total tumour load, TTL) has been shown to correlate with disease-free, local recurrence-free and overall-survival. We assessed the utility of OSNA TTL as a substitute for histological axillary node staging in determining prognosis within two prediction models.

Trefoil factor 1 in early breast carcinoma: a potential indicator of clinical outcome during the first 3 years of follow-up.

Background. A role of an estrogen-regulated, autocrine motogenic factor was assumed to be a major biological role of trefoil factor 1 (TFF1) in breast cancer. TFF1 is regarded as a predictive factor for positive response to endocrine therapy in breast cancer patients. The aim of our study was to examine TFF1 level distribution in breast carcinomas in order to distinguish estrogen-independent from estrogen-dependent TFF1 expression and to evaluate clinical usefulness of TFF1 status in early breast cancer during the first 3 years of follow-up.Methods. The study included 226 patients with primary operable invasive early breast carcinomas for whom an equal, a 3-year follow-up was conducted. TFF1 levels as well as estrogen receptor (ER) and progesterone receptor (PR) levels were measured in cytosolic extracts of tumor samples by immunoradiometric assay or by use of classical biochemical method, respectively. Non-parametric statistical tests were applied for data analyses.Results. Statistical analysis revealed that TFF1 levels were significantly higher in premenopausal patients (p=0.02), or in tumors with: lower histological grade (p<0.001), positive ER or PR status (p<0.001, in both cases). On the basis of TFF1 level distribution between ER-negative and ER-positive postmenopausal patients with tumors of different histological grade, 14 ng/mg was set as the cut-off value to distinguish estrogen-independent from estrogen-dependent TFF1 expression in breast cancer. Depending on menopausal and PR status, positive TFF1 status identified patients at opposite risk for relapse among ER-positive patients with grade II tumors. Among ER- and PR-positive premenopausal patients with grade II tumors, TFF1 status alone identified patients at opposite risk for relapse.Conclusions. Determination of TFF1 status might identify patients at different risk for relapse and help in making decision on administering adjuvant therapy for early breast cancer patients during the first 3 years of follow-up.

Cathepsin D as an Indicator of Clinical Outcome in Early Breast Carcinoma During the First 3 Years of Follow-Up

The aim of this study was to evaluate clinical usefulness of cathepsin D status in early breast cancer during the first 3 years of follow-up. The study included 226 patients with histologically verified, primary operable invasive early breast carcinomas. Concentrations of estrogen receptor (ER) and progesterone receptor (PR) in breast tumor cytosols were measured by use of the classical biochemical method. The concentration of three cathepsin D forms (52-, 48- and 34-kDa proteins) was determined by a radioimmunoassay On the basis of differences in cathepsin D levels either within an ER(-)/PR(-) phenotype or between this and either ER(+)/PR(+) or ER(+)/PR(-) phenotypes, a concentration of 39 pmol/mg was determined as the cutoff value for distinguishing estrogen-regulated cathepsin D expression. Estrogen-regulated cathepsin D expression was recognized as a high-risk biomarker for low-risk (histological grade I) breast cancer patients and as a low-risk biomarker for high-risk patients (pN(+) pT2,3). Determination of cathepsin D status in breast cancer might identify patients at different risk for relapse and might facilitate the selection of more or less aggressive adjuvant therapy for early breast cancer patients during the first 3 years of follow-up.

Neoadjuvant therapy for breast cancer has no benefits on overall survival or on the mastectomy rate in routine clinical practice. A population-based study with a median follow-up of 11 years using propensity score matching

BackgroundEven though neoadjuvant chemotherapy has shown no benefits on overall survival (OS), it is being widely used in the treatment of breast cancer. This is based on the assumption that it may diminish the mastectomy rate and therefore be clinically relevant for patients. Our objective was to assess the impact of neoadjuvant chemotherapy on OS and on the rate of mastectomy in patients with non-metastatic primary operable breast carcinoma in routine practice. MethodsThe Cote d’Or district breast cancer registry was used to analyse the OS and mastectomy rate in patients with invasive primary operable unilateral breast cancer diagnosed between 1982 and 2006. We performed Cox proportional hazard ratio (HR) analyses for OS and multivariate logistic regression for the mastectomy rate for the overall population. Different matching methods based on the propensity score were used as sensitivity analyses to ensure that corrections for selection bias were adequate. ResultsWe analysed 1578 patients, among whom 174 had received neoadjuvant chemotherapy. Median follow-up was 11.1years. There was no difference between the two treatment groups for OS (HR=1.08 (95% confidence interval (CI): 0.77–1.51 for neoadjuvant chemotherapy)). The mastectomy rate was higher among patients treated with neoadjuvant chemotherapy (odds ratio 1.54 (95%CI: 1.03–2.31)). Sensitivity analyses confirmed these results: for OS, there was no difference between the two populations precisely matched using propensity scores (HR 1.08; 95%CI: 0.671–1.65). ConclusionDespite long term follow-up, neoadjuvant chemotherapy provided no benefit for either OS or the mastectomy rate in our population.

Assessment of the axilla in primary operable breast carcinoma

The purpose of this study was to analyse assessment of the axilla in patients with primary operable breast cancer in a one-stop symptomatic breast unit.

Age related association of Her-2/neu with prognostic markers in female breast carcinoma.

To determine age-related association of Her-2/neu expression with histological and immunohistochemical prognostic markers in female breast carcinoma. Cross sectional, observational study. Department of Histopathology, Armed Forces Institute of Pathology, Rawalpindi, from January 2004 to December 2007. Patients of primary operable female breast carcinoma were categorised as < 40 years (pre-menopausal), 41-50 years (peri-menopausal) and > 50 years (post-menopausal) age groups. Histological type, tumour size, tumour grade and lymph node status were determined while estrogen receptor (ER), progesterone receptor (PR) and Her-2/neu expression were evaluated immunohistochemically. Association of Her-2/neu with histological and immnuohistochemical prognostic markers was determined in pre-menopausal, peri-menopausal and post- menopausal age groups using the x2 test for uni- and multivariate analysis. Out of the 722 patients, 230 (31.9%) were in pre-menopausal, 221 (30.6%) in peri-menopausal and 271 (37.5%) in post-menopausal age group. Infiltrating ductal carcinoma was the pre-dominant subtype in all the age groups. Mean tumour size was 4.3+/-2.3 cm (range 0.4-17 cm) and lymph node metastasis was seen in 310 (70.8%) cases. Her-2/neu showed association with ER in the all the age groups while PR only showed association in the peri-menopausal and postmenopausal women. Her-2/neu showed no association with tumour size, tumor grade and lymph node metastases in pre-menopausal and peri-menopausal women while it showed positive association with tumour size and lymph node metastasis in the post-menopausal women (p < 0.05). Majority (62%) patients were under 50 years as against the Western epidemiology. Association of Her-2/neu with ER, PR, tumour size and lymph node metastasis was age related as pre-menopausal, peri-menopausal and postmenopausal had variable expression of these prognostic markers with therapeutic and prognostic implications.

MIB1/Ki-67 labelling index can classify grade 2 breast cancer into two clinically distinct subgroups

Histological grade is recognized as one of the strongest prognostic factors in operable breast cancer (BC). Although grade 1 and grade 3 tumours are biologically and clinically distinct, grade 2 tumours bear considerable difficulty in outcome prediction and planning therapies. Several attempts such as genomic grade index have been performed to subclassify grade 2 into two subgroups with clinical relevance. Here, we present evidence that the routinely evaluable immunohistochemical MIB1/Ki67 labelling index (MIB-LI) can classify grade 2 tumours into two clinically distinct subgroups. In this study, growth fractions of 1,550 primary operable invasive breast carcinomas were immunohistochemically assayed on full-face tissue sections using the MIB1 clone of Ki-67. Growth fractions were assessed as number of MIB1 positive nuclei in 1,000 tumour nuclei at high-power magnification and expressed as MIB1-LI. Using a 10% cut-point of MIB1-LI, grade 2 BCs were classified into low (49.8%) and high (50.2%) proliferative subgroups. Univariate and multivariate survival analysis revealed statistically significant differences between these subgroups regarding patients' BC specific survival (P < 0.001), and metastasis free survival (P < 0.001) which was independent of the well-established prognostic factors (HR = 2.944, 95% CI = 1.634-5.303, P < 0.001). In conclusion, our results further demonstrate that grade 2 BCs may represent at least two biological or behaviourally different entities. Assay of growth fraction in BC using MIB1/Ki67 immunohistochemistry is a robust cost-effective diagnostic tool that subdivides grade 2 tumours into low and high risk populations providing additional prognostic information in planning therapies and outcome prediction.

Steroid hormone receptor association with prognostic markers in breast carcinoma in Northern Pakistan.

To determine steroid hormone receptor expression and their association with histological prognostic markers and biological profile in female breast carcinoma in Northern Pakistan. Cross sectional, observational. Department of Histopathology, Armed Forces Institute of Pathology, Rawalpindi, from January 2004 to December 2007. Female patients belonging to Northern Pakistan with primary operable breast carcinoma were included in the study. Patient's age, microscopic tumour size, tumour grade, lymph node status and biological profile for Her-2/neu status were evaluated. Immunohistochemical expression for ER and PR was determined individually and conjointly for ER+PR+ and ER-PR- while their association with above prognostic markers was determined using the c2 test for univariate analysis. Out of the 726 cases, there were 657 (90.4%) cases of infiltrating ductal carcinoma with mean age of 48+/-12 years and mean tumour size of 4.2+/-2.3 cm. Tumour was grade-II in 65% and lymph node metastases in 71.5% cases with Her-2/neu+ in 28.1%. ER and PR expression was 74.6% and 68.3% respectively. Conjoint expression of ER+PR+ was 456 (62.8%), ER-PR- in 21.2%, ER+PR- in 86 (11.8%) and ER-PR+ in 30 (4.1%) cases. Individually, ER and PR showed positive association with age, lymph node metastasis, tumour grade and inverse association with Her-2/neu. Conjoint expression of ER+PR+ (62.8%) and ER-PR-(21.2%) showed positive association with age, tumour grade, lymph node metastasis and inverse association with Her-2/neu (p < 0.05). Hormone receptor expression of ER and PR expression is comparable to the West with ER and PR showing inverse association with Her-2/neu and positive association with age, tumour grade and lymph node metastases.

Morphological profile and association of HER-2/neu with prognostic markers in breast carcinoma in Northern Pakistan.

To determine the morphological profile and association of HER-2/neu expression with histological prognostic markers and hormonal receptor expression in female breast carcinoma in Northern Pakistan. Cross-sectional, observational study. Department of Histopathology, Armed Forces Institute of Pathology, Rawalpindi, from January 2004 to May 2007. A total of 535 patients of primary operable female breast carcinoma with hormonal profile and biological status were included in the study. Patient's age, microscopic tumour size, tumour grade, lymph node status, Estrogen Receptor (ER), Progesterone Receptor (PR) and joint ER/PR status were evaluated and their association was determined with HER-2/neu expression using the x2 test for univariate analysis. Out of 535 cases, there were 481 (89.9%) cases of infiltrating ductal carcinoma with mean age of 48 years and mean tumour size of 4.4 cm. Tumour grade II was seen in 68% cases and lymph node metastases were present in 65% cases. HER-2/neu expression was seen in 31% cases, while ER and PR expression was seen in 72.3% and 62.6% respectively. ER and PR showed inverse association with HER-2/neu while positive association was seen with lymph node metastases (p < 0.05). No association was seen between tumour size and tumour grade. Joint ER and PR expression also showed a higher number (73.5%) of HER-2/neu negative cases. HER-2/neu, ER and PR expression is comparable to the West with inverse association with ER and PR and positive association with lymph node metastases. Since HER-2/neu expression is variable in carcinomas with different tumour characteristics, it is not possible to predict hormone receptor expression in all the cases.

A multicentric analysis and an introduction of a German prospective study to evaluate the value of sentinel node excision after neoadjuvant chemotherapy

Sentinel lymph node biopsy (SLNB) without further axillary dissection in patients with sentinel node-negative breast carcinoma appears to be a safe procedure to ensure locoregional control. During a median follow-up of 35 months the false-negative rate was 1% in our study population of 185 patients.Background. The objective of this prospective study is to provide data on follow-up of patients with primary operable breast carcinoma staged with SLNB without axillary lymph node dissection (ALND) if the sentinel lymph nodes (SLNs) were tumour-negative.Methods. One hundred and eighty-five patients were enrolled. Preoperative dynamic and static lymphoscintigraphy were performed; both a vital blue dye and a gamma detection probe were used intraoperatively. Patients with tumour-positive SLNs received completion ALND or if no SLNs could be identified. All patients were monitored according to regional follow-up protocols.Results. The SLNs were identified in 179 out of the 185 patients. In 73 patients the SLNs were tumour-positive and in 106 patients tumour-negative. The median follow-up was 35 months (range 17–59). In one SLN-negative patient an axillary recurrence occurred 26 months after the SLNB (false-negative rate: 1%).Conclusions. SLNB without ALND appears to be a safe procedure to ensure locoregional control in SLN-negative breast carcinoma, if carried out by an experienced team.

Long-term results of breast conserving surgery vs. mastectomy for early stage invasive breast cancer: 20-year follow-up of the Danish randomized DBCG-82TM protocol

The main objective of the present study aims at comparing the long-term efficacy of breast conserving surgery (BCS) vs. mastectomy (M) based on a randomized design. The Danish Breast Cancer Cooperative Group (DBCG) conducted the trial (DBCG-82TM) from January 1983 to March 1989 recruiting 1154 patients with invasive breast carcinoma. Follow-up time ended 1st May 2006 with a median follow-up time of 19.6 years (time span 17.1–23.3 years). Eligibility criteria included a one-sided, unifocal, primary operable breast carcinoma, patient age below 70 years, probability of satisfactory cosmetic outcome with BCS, and no evidence of disseminated disease. The patients accrued were grouped into three subsets: correctly randomized, suspicion of randomization error, and declining randomization.The main analyses focus on the subgroup of 793 correctly randomized patients representing 70% of the complete series. 10-year recurrence free survival (RFS) and 20-year overall survival (OS) based on intent to treat did not reveal significant differences in outcome between breast conserving surgery vs. mastectomy, p=0.95 and p=0.10, respectively. Including the complete series comprising 1133 eligible patients based on treatment in fact given similarly no significant difference between surgical options could be traced in outcome of 10-year RFS and 20-year OS, p=0.94 and p=0.24, respectively.The pattern of recurrences as a first event in breast conservation vs. mastectomy did not differ significantly irrespective of site, p=0.27. Looking into the type of local relapse, viz., new primaries vs. true recurrences, it appeared that new primaries were significantly associated to BCS, while true recurrences dominated among M treated patients (p<0.001).In conclusion, long-term data indicate that BCS in eligible patients proves as effective as mastectomy both regarding local tumour control, RFS and OS. Local failures as a first event consistent with new primaries are strongly associated with BCS, whereas true recurrence predominates after mastectomy.

The role of estrogen receptors isoforms in breast cancer

Background: Estrogen and progesterone receptor (ER/PR) status is an accepted predictive marker in breast cancer. It is well known that breast tumors, which are ER(+) are more likely to respond to endocrine therapy. However, certain percentage of ER(+)/PR(+) tumors do not respond to endocrine therapy. Identification of the second estrogen receptor, named estrogen receptor beta (ER?), as well as the existence of numerous isoforms/splice variants of both ER? and ER?, suggests that complex regulation of estrogen action exists. In this study, we analyze does the expression of two ER? isoforms correlates with ER?/PR status. Methods: Sixty samples of primary operable breast carcinomas were analyzed for ER? and PR protein levels and for mRNA expression of two ER? isoforms (ER?1 and ER??5). ER? and PR proteins were measured by classical biochemical techniques, and ER? mRNAs were measured by real-time RT-PCR. Results: Tumors are divided in three groups according to relative level of mRNA for ER?1 and ER??5. We found that there is no correlation of ER?1 mRNA expression with ER? and PR protein levels. We confirmed the existence of inverse correlation of ER??5 with PR and of ER??5 with ER? in the group of postmenopausal patients. In the subsets of tumors defined by ER?/PR status, we found that percentage of tumors, which concomitantly expressed high levels of both transcripts, are parallel with those that do not response to tamoxifen treatment. Conclusion: Inverse correlation of ER? with ER??5 and PR with ER??5isoform suggests that ER??5 may have inhibitory effect on ER? activity in postmenopausal patients. In addition, we point out that determination of expression profiles of ER? and ER? isoforms in the defined groups of patient are necessary for elucidating its involvement in endocrine resistance. .

Probability of false negative nodal staging in conjunction with partial axillary dissection in breast cancer.

There is a risk of overlooking lymph node metastases and thereby contributing to inaccurate nodal staging when performing partial axillary dissection in conjunction with total mastectomy in female breast cancer. The Danish Breast Cancer Cooperative Group (DBCG) analysed this risk in a prospective nation-wide adjuvant trial dealing with primary operable breast carcinoma. The series comprised 3114 patients, initially found to have lymph node negative axillae, followed for a median of 24 months (quartiles 12-40). It was found that the probability of early ipsilateral axillary relapse of cancer, estimated by means of the life table method, decreased with the number of nodes removed. After 2 years the recurrence rate was 12 per cent for patients with no lymph nodes removed, 7 per cent with one or two nodes removed and 2 per cent with three or more nodes removed. It is concluded that the risk of false negative nodal staging in conjunction with partial axillary dissection is modest, provided at least three lymph nodes are removed and found to be negative on histological examination.

Prognostic significance of peritumoral vascular invasion in patients with invasive breast cancer

Purpose: Multiple clinical, biological, and pathologic factors correlate with the outcomes in patients with invasive breast cancer. The utility of a peritumoral vascular invasion (PVI) as an additional prognostic indicator has been poorly defined. The aim of this study was to determine if the presence or absence of PVI can be used to help assess the survival and recurrence. Methods: An invasion of the vascular space (lymphatic and/or blood vessel) by a tumor, as assessed on routine hematoxylin and eosin sections, was investigated in a 146 women with primary operable invasive breast carcinoma. The presence of PVI was compared with the established prognostic factors such as age, tumor size, axillary lymph node involvement, histological grade, hormonal receptor status, and expression of c-erb B2, Ki-67 and p53. Survival analysis was performed using Kaplan-Meier method and log-rank test. Results: PVI was found in 35.6% of cases and was significantly associated with an increasing tumor size (P=0.033) and metastatic axillary lymph nodes (P=0.012). The 5 year disease free survival (DFS) and overall survival (OS) were significantly lower in the patients with PVI than without PVI (P=0.0431 and 0.0445, respectively). In multivariate analysis, the axillary lymph node status (P=0.001), the tumor size (P=0.044) and PVI (P=0.050) were significant independent prognostic factors for the DFS. In the nodenegative breast cancer group and in the node-positive breast cancer group, the 5 year DFS and OS were lower in the patients with PVI than in those without, but this did not show significant difference. Conclusion: Cox multivariate analysis showed that PVI is a strong prognostic factor for patients with operable invasive breast cancer and an independent prognostic factor for a recurrence. A histological assessment of PVI can provide prognostic information on primary operable invasive breast carcinoma and might be helpful in making a clinical decision. (Journal of Korean Breast Cancer Society 2004;7:166-173)

Axillary recurrence after sentinel lymph node biopsy

Sentinel lymph node biopsy (SLNB) without further axillary dissection in patients with sentinel node-negative breast carcinoma appears to be a safe procedure to ensure locoregional control. During a median follow-up of 35 months the false-negative rate was 1% in our study population of 185 patients. Background. The objective of this prospective study is to provide data on follow-up of patients with primary operable breast carcinoma staged with SLNB without axillary lymph node dissection (ALND) if the sentinel lymph nodes (SLNs) were tumour-negative. Methods. One hundred and eighty-five patients were enrolled. Preoperative dynamic and static lymphoscintigraphy were performed; both a vital blue dye and a gamma detection probe were used intraoperatively. Patients with tumour-positive SLNs received completion ALND or if no SLNs could be identified. All patients were monitored according to regional follow-up protocols. Results. The SLNs were identified in 179 out of the 185 patients. In 73 patients the SLNs were tumour-positive and in 106 patients tumour-negative. The median follow-up was 35 months (range 17–59). In one SLN-negative patient an axillary recurrence occurred 26 months after the SLNB (false-negative rate: 1%). Conclusions. SLNB without ALND appears to be a safe procedure to ensure locoregional control in SLN-negative breast carcinoma, if carried out by an experienced team.

Extent of ductal carcinoma in situ within and surrounding invasive primary breast carcinoma.

The aim of this study was to evaluate the pathological and morphological features of ductal carcinoma in situ (DCIS) within and surrounding invasive ductal carcinoma, and to investigate its relationship with clinical outcome and established prognostic variables. One hundred and seven patients with primary operable invasive breast carcinoma and associated DCIS treated by simple or subcutaneous mastectomy or wide local excision with radiotherapy were assessed. Those with pure DCIS and insufficient tumour available for examination were excluded. The most representative haematoxylin and eosin-stained sections from the remaining 91 samples were selected and examined at x 100 magnification using a 45-point, 2-mm grid graticule. The entire section was assessed and the cell under each point of the graticule was classed as either normal (a), DCIS surrounded by normal tissue (b), invasive tumour (c) or DCIS surrounded by invasive malignancy (d). The volume ratio of DCIS in the normal (b/(a + b)) and invasive (d/(c + d)) tissue was then calculated. The DCIS volume within invasive tumour was not associated with outcome. The DCIS volume within adjacent normal tissue, however, was associated with local recurrence (P = 0.025), disease-free interval (P = 0.048), the occurrence of distant metastases (P = 0.019), death (P = 0.049) and disease-free survival (P = 0.048). Volume ratios of DCIS in normal and invasive tissue were not related to known prognostic factors including lymph node stage, grade, tumour size, vascular invasion or patient age. There is a significant prognostic effect relating to the extent of DCIS associated with an invasive cancer, particularly with respect to local recurrence of tumour. This effect is restricted to the volume of DCIS in the tissue surrounding the invasive lesion rather than the intratumoral component.

Detecting which invasive cancers at mammographic screening saves lives?

Assessment of the features of primary operable breast carcinomas arising in women known to subsequently develop metastatic disease, to show for which invasive breast cancers earlier detection by mammographic screening is potentially beneficial. These data were applied to a separate series of screen detected cancers. Features associated with the development of metastatic disease after a previous operable breast cancer were ascertained from examination of histological sections of the initial primary carcinoma and in particular the incidence of nodal positivity and definite vascular invasion. Trends in the frequency of nodal involvement and vascular invasion according to histological grade, invasive size, and tumour type were then examined in a further group of 573 screen detected invasive cancers to predict the likelihood of development of systemic disease in these women. Of 173 women who developed metastatic disease after a previous operable breast cancer, 79 (72%) had nodal metastases and 62 (59%) had definite vascular invasion. A high proportion (84%) had either lymph node metastases or vascular invasion or both. The absence of vascular invasion and nodal involvement in invasive breast cancer indicated a low risk of subsequent development of metastatic disease. In the screen detected group, grade 1 invasive cancers <20 mm in size and grade 2 and 3 cancers <10 mm in size had low rates of nodal involvement and vascular invasion. There was a gradual trend to small size, lymph node negativity, and less vascular invasion when comparing screen detected ductal carcinoma of no special type, tubular mixed carcinoma, and tubular carcinoma. Cancers with a lobular component tended to be larger and more often lymph node positive than ductal and no specific type carcinomas. These data suggest that identification of grade 1 cancers less than 20 mm in size and grade 2 and 3 cancers less than 10 mm in size at screening is likely to be beneficial, with a lower likelihood of developing metastatic disease from these lesions. The detection of tubular mixed carcinomas and ductal carcinomas of no specific type also appears beneficial. However the detection of tumours with lobular features at breast screening does not seem to significantly benefit the patient.

Apoptosis and proliferation as predictors of chemotherapy response in patients with breast carcinoma

BACKGROUND Laboratory evidence suggests that many anticancer agents exert their effect by altering the ratio between apoptosis and cellular proliferation. The objective of this clinical study was to examine in vivo changes in apoptotic index (AI), Bcl-2 expression, proliferation (Ki-67 and S-phase fraction [SPF]), and ploidy as potential indicators of chemoresponsiveness. METHODS Twenty-eight women with primary operable breast carcinoma received 2M (mitoxantrone 11 mg/m2, methotrexate 35 mg/m2 every 3 weeks) for 4 cycles before surgery/radiotherapy, and an additional 2 cycles were given after surgery. Clinical response was assessed after four cycles of treatment according to World Health Organization criteria. Changes in molecular markers were assessed from biopsies obtained by fine-needle aspiration performed before treatment, repeated after 24 and/or 72 hours (T1), and on Days 7 and 21 after the first cycle of chemotherapy. Flow cytometric analysis was used to assess SPF, ploidy, and AI (in situ DNA nick end labeling assay) whereas Ki-67 and Bcl-2 were evaluated by immunocytochemical analysis. RESULTS The overall response rate was 61% (17 of 28 patients), with a 14% (4 of 28 patients) complete response rate. Patients with diploid carcinomas (P = 0.04) with high Ki-67 (P = 0.0001) and SPF (P = 0.09) were more likely to respond to treatment. Median AI increased by 3.4% with interquartile (IQ) range of 3.2 in responders, compared with only −0.1% (IQ range, 2.2) in nonresponders at T1 (P = 0.03). Median Ki-67 decreased by −12.0% (IQ range, 22.9) in responders and increased by 18.5% (IQ range, 15.1) in nonresponders on Day 21 (P = 0.003). Median Bcl-2 scores increased by 1.0 (IQ range, 4.0) in responders and were unchanged at 0.0 (IQ range, 0.5) in nonresponders (P = 0.08). Changes in SPF or ploidy were not significantly predictive of response. CONCLUSIONS The results of this preliminary study support evidence that chemotherapy may increase apoptosis, decrease Ki-67, and increase Bcl-2 expression in primary breast carcinomas that subsequently respond to therapy. Methodology allowing morphological confirmation of apoptosis would be advantageous. Cancer 2000;89:2145–52. © 2000 American Cancer Society.

C-erbB-4 protein expression in human breast cancer.

The Type 1 family of growth factor receptors includes epidermal growth factor receptor (EGFR), c- erb B-2, c- erb B-3 and c- erb B-4. Overexpression of the first two members is associated with poorer prognosis in patients with breast carcinoma. In this study we examined the expression of c- erb B-4 protein using the monoclonal antibody HFR-1. A total of 127 consecutive cases of primary operable invasive breast carcinoma presenting between 1975 and 1977 were studied. All patients were managed by simple mastectomy or conservation surgery with radiotherapy and no adjuvant therapy given. Long-term follow-up was maintained. Routine, formalin-fixed, paraffin-embedded tumour samples were used and sections were stained immunohistochemically using the Duet StreptABC method. Immunoreactivity was classified using a simple semi-quantitative scoring method. Protein expression was generally low but definite positive cytoplasmic, membranous and nuclear reactivity was identified in 58%, 41% and 25% of cases respectively. Expression at all three sites demonstrated significant inverse associations were histological grade. In addition, membrane accentuation correlated inversely with the Nottingham Prognostic Index (NPI), while cytoplasmic reactivity showed a positive association with c- erb B-3 expression. No significant associations were found with disease-free interval or survival. The results of this study demonstrate that higher levels of c- erb B-4 protein expression are associated with a more differentiated histological phenotype in contrast to the other members of the Type 1 family. Larger series with extended follow-up will be required to ascertain definitively the prognostic value of c- erb B-4 expression in breast carcinoma. © 2000 Cancer Research Campaign