Clive Griffith

Biomarker Changes During Neoadjuvant Anastrozole, Tamoxifen, or the Combination: Influence of Hormonal Status and HER-2 in Breast Cancer—A Study from the IMPACT Trialists

PURPOSE To investigate the relationships between biomarker changes in breast cancer during neoadjuvant (preoperative) endocrine therapy. PATIENTS AND METHODS The IMPACT trial compared the preoperative use of tamoxifen with anastrozole alone or in combination in postmenopausal women (n = 330) with primary breast cancer. Biomarkers were measured in tumor biopsy specimens taken at baseline, and after 2 and 12 weeks of treatment. RESULTS 52 (93%) of 56, 46 (85%) of 54, and 37 (84%) of 44 patients in the anastrozole, tamoxifen, and combination groups, respectively. There was a significantly greater suppression of Ki67 in the anastrozole-treated group than in the tamoxifen- or combination-treated groups, which is parallel to the greater efficacy seen for anastrozole over these two treatments in the Arimidex, Tamoxifen, Alone or in Combination adjuvant trial. A positive relationship was noted between estrogen-receptor level and Ki67 suppression in all patients. Ki67 was reduced to a greater extent in progesterone receptor-positive tumors compared with progesterone receptor-negative tumors. HER-2-negative tumors tended to show a greater reduction in Ki67 compared with HER-2-positive tumors, but the difference was only significant in the tamoxifen group after 2 weeks, and in the anastrozole group after 12 weeks. CONCLUSION These results confirm the value of Ki67 as a molecular marker, and provide information regarding the relationships between treatment-induced changes in Ki67 and other important biomarkers. Studies such as this should help integrate agents targeted at growth factor signaling with endocrine agents in breast cancer.

Proliferation and Apoptosis as Markers of Benefit in Neoadjuvant Endocrine Therapy of Breast Cancer

The study of changes in proliferation as a marker of treatment benefit during presurgical endocrine treatment of breast cancer has become increasingly popular, particularly using the nuclear marker Ki67, and holds the potential for prioritizing new treatments for full clinical development. There are weakly significant relationships between Ki67 change and clinical response that differ according to data handling. In the neoadjuvant Immediate Preoperative Anastrozole, Tamoxifen, or Combined with Tamoxifen trial, suppression of Ki67 at both 2 and 12 weeks was greater with the aromatase inhibitor anastrozole than with either tamoxifen or the combination of anastrozole and tamoxifen. We report here that absolute values of Ki67 after 2 weeks were also significantly lower with anastrozole than with tamoxifen and the combination. This indicates that it may be possible to make such comparisons using surgical samples only. We argue that these changes in proliferation and concurrent changes in apoptosis may be expected to be more predictive of adjuvant benefit from endocrine therapy than clinical response.

Granulomatous mastitis can mimic breast cancer on clinical, radiological or cytological examination: a cautionary tale

In both women and men, breast lumps are the most common presentation of breast cancer. The following cases illustrate the pathological entity of granulomatous mastitis, which can present simulating breast cancer - including the first description of this condition in a male. These cases demonstrate the difficulty in clinical diagnosis and emphasizes that although there may be clues from the history, clinical awareness that this condition can mimic breast cancer in all aspects of the triple assessment process should arouse suspicion. The importance of histological diagnosis by core or excision biopsy is stressed, as with accurate diagnosis of granulomatous mastitis there is a mandate to avoid unnecessary surgery.

p53 protein expression in ductal carcinoma in situ (DCIS) of the breast

Abnormalities in p53 gene expression have been implicated in many inherited and sporadic forms of malignancies in humans. Immunohistochemical staining using monoclonal antibody D0–7 for the p53 protein expression was performed in 81 cases of pure DCIS, 14 benign breast lesions and 2 cases with normal breast tissue. Expression of p53 protein was detected in 15 (18.5%) cases of pure DCIS. Thirteen (25%) of the 52 comedo type DCIS showed p53 protein expression compared with 2 (6.9%) of the 29 non-comedo types (P < 0.02). p53 protein expression was also associated with high nuclear grade (P < 0.001) and high mitotic index (P < 0.05). The pattern of p53 protein staining was diffuse in one comedo type DCIS, regional in 6 comedo types, and focal in the remaining 8 cases (6 comedo type and 2 micropapillary type DCIS). The patient with comedo type DCIS showing diffuse staining has a family history of breast cancer in the first and second degree relatives (sister and maternal aunt). Clinical follow-up data was available in 52 cases. Follow-up period ranged from 9 to 55 months. Three patients, who were primarily treated by local excision, have had a documented local recurrence in the form of residual tumor within a short interval of 5 to 11 months. In all these three patients both the original and the recurrent tumors are negative for p53 protein expression. The difference in the local recurrence rate between p53 positive (0/15) and p53 negative (3/37) cased does not reach statistical significance (p > 0.05). We interpret that the local tumor recurrence in these three cases within a short period after primary excision is due to the presence of residual tumor at the excision site and is independent of the p53 gene alteration. It is concluded that p53 protein expression in DCIS is associated with comedo subtype, high nuclear grade, and high mitotic index, and is a promising new parameter to evaluate the cellular biology and prognosis of DCIS.

Sentinel lymph node biopsy in early breast cancer surgery – Working with the risks of vital blue dye to reap the benefits

AIMS Sentinel lymph node biopsy (SLNB) is an important method of staging early breast cancer because of the inherent benefits it confers on patients in terms of arm function and quality of life. Its success depends on a high level of accuracy in detecting the sentinel node. This is achieved by a dual mapping technique that employs a radio-labelled nanocolloid and a vital blue dye. The vital dyes however carry the risk of anaphylaxis, and as more surgeons employ SLNB in their daily practice, a proportionate rise in the number of anaphylactic reactions can be expected. A comprehensive review of risks and benefits associated with using vital blues dyes has not been published and therefore a retrospective review was undertaken of the different levels of anaphylaxis associated with vital dyes as well as their benefits in SLNB. METHODS An OVID MEDLINE search was performed of the English published literature using appropriate search terms to find published trial data and case series that focused on adverse reactions to vital blue dyes. RESULTS The risk of severe anaphylaxis (grade 3) can be as low as 0.06%, and up to 0.4% for patients undergoing SLNB when data is analysed from large trials. Furthermore, adverse reactions associated with blue dyes are reversible with appropriate management. CONCLUSIONS Surgeons should continue to use vital dyes to ensure that SLNB remains a highly sensitive procedure.

Tumour bed biopsy detects the presence of multifocal disease in patients undergoing breast conservation therapy for primary breast carcinoma

This study prospectively examined tumour bed biopsies in 135 consecutive patients undergoing conservative surgery for breast carcinoma. All had wide resection of the primary tumour and histologically clear margins. Twelve patients (9%) had positive tumour bed biopsies. Two subgroups of patients had positive bed biopsies; those with ductal carcinoma in situ, and a second group with more aggressive disease characterized by lymph node involvement, vascular invasion and a higher grade and mitotic count. As the majority of recurrences from breast carcinoma occur in the region of the primary tumour, bed biopsy may aid in the identification of a group of patients with multifocal or aggressive disease who are at increased risk of local recurrence.

Size does matter: High volume breast surgeons accept smaller excision margins for wide local excision – A national survey of the surgical management of wide local excision margins in UK breast cancer patients

INTRODUCTION Optimal margins for wide local excision (WLE) have not been clearly established. Larger margins lead to lower recurrence rates but at the expense of cosmetic appearance. NICE guidelines recommend a 2 mm margin for ductal carcinoma in-situ (DCIS), whilst the British Association of Surgical Oncology (BASO) recommend units develop local guidelines. There are presently no specific guidelines for invasive cancer. We surveyed members of the Association of Breast Surgeons (ABS) in order to establish current practice nationally. We hypothesised that larger units may accept narrower excision margins to the benefit of better cosmesis. MATERIALS AND METHODS A postal questionnaire was sent to all ABS members in October 2010. This consisted of questions about the current practice of the surgeon and their unit. 481 questionnaires were posted in total, all questionnaires returned by April 2011 were analysed. RESULTS Questionnaire response rate was 60% (281). Surgeons operating on over 50 cancers per year accepted smaller margins than those operating on less than 50 (p < 0.02). Acceptable adequate anterior and radial margins ranged from 0 to 10 mm for DCIS and 0 to 5 mm for invasive cancer. A variety of approaches to re-excising anterior margins were reported. CONCLUSIONS This survey suggests that substantial variations exist in current practice with regard to the approach to WLE. Operator workload appears to influence what is deemed to be an acceptable margin. There is a need for standardised national and international guidelines.

Serum adrenal androgens in women with primary operable breast cancer and their relationship with age and body mass index

Abstract Several studies have found elevated levels of adrenal androgens in postmenopausal women and depressed levels in premenopausal women with breast cancer, suggesting a role for adrenal androgens in the aetiology of breast cancer. We have measured serum dehydroepiandrosterone sulphate and androstenedione in 81 women with primary operable breast cancer and 62 age-matched controls. Results showed that serum levels of both adrenal androgens fell significantly with age in women with breast cancer ( P =0.003). However, no relationship was observed between serum adrenal androgen levels and body mass index in either women with breast cancer or controls. Dehydroepiandrosterone sulphate levels were elevated in postmenopausal women with breast cancer compared to controls, and this was not due to preoperative stress. No differences were observed in androstenedione levels between premenopausal or postmenopausal women with breast cancer and controls, nor were dehydroepiandrostenedione sulphate levels significantly different between premenopausal women with breast cancer and controls. These results suggest that dehydroepiandrosterone sulphate has a role in the aetiology of postmenopausal breast cancer.

272 POSTER Mastectomy versus breast conservation rate for breast cancer; the breast surgeon is an independant variable factor

Background: The rate of mastectomy versus breast conserving surgery is an audit measure for breast units in the UK for both symptomatic and screen detected breast cancer patients.There are wide variations between units in the UK. Patients and Methods: 1009 women who had surgical treatment for breast cancer (580 screen detected,429 symptomatic)in our unit from Jan2004Dec2005 were included in this study.Data was obtained from multidisiplinary team meeting reports and our audit database. Results:

How good is needle biopsy for microcalcification in an unselected clinic population ('the real world')?

Recently a set of ten adjustments that optimizes the prognostic strength of both DNA ploidy (P) and S-phase (S) was published (Cytometry, 46(3), 2001). Also presented was an optimal method of combining P and S (P+S) that stratifies node-negative patients into highly significant risk groups. The adjustments compensate for many unappreciated complexities in categorizing P into low and high risk groups and eliminate unwanted correlation between P and S. The purpose of this study is to examine P+S in the context of other well-known prognostic factors such as primary size (pT), estrogen and progesterone receptor (ER,PR) and menopausal status (MS). Methods: DNA histograms derived from frozen primary tumors and clinical databases were provided by Baylor College, n=935; Sweden, n=210 (Lund, Linkoping, Stockholm) and France, n=220 (Angers, Marseille, Saint Cloud, Tours). Time to metastasis was the tested clinical outcome. Results: Cox proportional hazards analysis of theBaylor data revealed P+S, p<0.000002, and pT, p<0.003, as independent significant prognostic factors. The Sweden study also showed P+S the mostsignificant prognostic factor, p<0.002, as well as MS, p<0.004 and ER, p<0.007. The French study results were MS, p<0.0005, P+S, p<0.002 and pT, p<0.007.A P+S, MS and pT prognostic model stratified patients in all studies into highly significant categories, Baylor, p<0.000005, Sweden, p<0.00001, and French, p<0.000005, with low and high risk 10-year relapse-free survival fractions of 0.92-0.69, 0.95-0.58 and 0.96-0.60 respectively. Conclusion: A combined P+S, MS and pT prognostic model is a powerful and reliable method of stratifying node-negative breast cancer patients into highly significant prognostic groups.Submission Deadline: June 1 every year MONDAY, DECEMBER 10, 2001