Multicentric breast cancer: clonality and prognostic studies.

Clonality of multicentric breast cancer has traditionally been difficult to assess. We aimed to assess this using analysis of TP53 status (expression and mutation status). These results were then incorporated into an analysis of prognostic factors in multicentric tumours in a 10-year follow up study. Clonal status of multicentric breast cancer foci (n = 88 foci) was determined by immunohistochemical and molecular studies of TP53 in a total of 40 patients. Prognostic factors from these patients were also compared with 80 age- and stage-matched controls with unicentric breast cancer from the Royal Marsden NHS Foundation Trust Breast Cancer Database. Our results indicate that multicentric breast cancer foci were polyclonal within an individual patient in at least 10 patients (25%) with respect to immunohistochemical staining and in four patients (10%) with respect to abnormal band shifts on single strand conformational polymorphism (SSCP) molecular analysis. No individual variable was predictive of multicentric or unicentric disease. However, there was a worse overall survival in the multicentric breast cancer patients in whom at least two cancer foci stained positively on TP53 immunohistochemistry compared with the matched control group (P = 0.04). In conclusion, these results suggest that a proportion of multicentric breast cancer foci are polyclonal with respect to TP53 status and that TP53 over-expression predicts for a poorer prognosis in multicentric breast cancer.

A randomised comparative trial of infusional ECisF versus conventional FEC as adjuvant chemotherapy in early breast cancer: the TRAFIC trial.

BACKGROUND: The epirubicin with cisplatin and infusional 5-fluorouracil (5-FU) (ECisF) regimen was found to be highly active in the treatment of metastatic breast cancer and as neoadjuvant therapy. The UK TRAFIC (trial of adjuvant 5-FU infusional chemotherapy) trial (CRUK/95/007) compared this schedule with 5-FU, epirubicin and cyclophosphamide (FEC60) as adjuvant therapy in patients with early breast cancer. METHODS: In this multicentre, open-label, phase III randomised controlled trial, 349 women were randomly assigned to receive i.v. ECisF [epirubicin 60 mg/m(2), day 1, cisplatin 60 mg/m(2), day 1 and 5-FU 200 mg/m(2) by daily 24-h infusion (n = 172)] or FEC [5-FU 600 mg/m(2), day 1, epirubicin 60 mg/m(2), day 1 and cyclophosphamide 600 mg/m(2), day 1 (n = 177)]. Both treatments were delivered every 3 weeks for six cycles. The primary end point was relapse-free interval (RFI). TRAFIC is registered as an International Standard Randomised Controlled Trial (ISRCTN 83324925). RESULTS: All randomised patients were included in the intent-to-treat population. With a median follow-up of 112 months, there was no significant difference in RFI between the treatment groups [hazard ratio 0.84 (95% confidence interval 0.60-1.19); P = 0.33]. Toxic effects were more frequent in patients allocated to ECisF. CONCLUSIONS: While limited by size, TRAFIC has long follow-up. No evidence of a clinically worthwhile benefit for the infusional treatment compared with standard treatment was observed which would justify further investigation or widespread use.

Changes in estrogen receptor, progesterone receptor, and pS2 expression in tamoxifen-resistant human breast cancer.

Changes in estrogen receptor (ER) expression and function may explain the development of tamoxifen resistance in breast cancer. ER expression was measured by an immunohistochemical assay, validated for use in tamoxifen-treated tumors against a biochemical enzyme immunoassay, in 72 paired biopsies taken before treatment and at progression or relapse on tamoxifen. Progesterone receptor (PgR) and pS2 gene expression were also measured immunohistochemically as an indicator of ER function. Overall the frequency of ER expression was reduced from 37 of 72 (51%) pretamoxifen to 21 of 72 (29%) at progression or relapse, with a significant reduction in the quantitative level of ER (P < 0.0001; Wilcoxon signed rank sum test). Tumors treated with primary tamoxifen that responded but then developed acquired resistance frequently remained ER positive (ER+) at relapse: 16 of 18 (89%) were ER+ pretamoxifen (75% of these expressed either PgR or pS2) and 11 of 18 (61%) were ER+ at relapse (82% continued to express PgR or pS2). In contrast, only 3 of 20 (15%) tumors that progressed on primary tamoxifen with de novo resistance were ER+ pretamoxifen, and all tumors were ER- at progression. At progression, 6 of 20 (30%) of these tumors expressed high levels of PgR (mean H-score, 98) and/or pS2 (mean, 50% cells positive), despite being ER-. In tumors that recurred during adjuvant tamoxifen therapy, including locoregional and metastatic lesions, ER expression was significantly reduced from 18 of 34 (53%) in the original primary tumor to 10 of 34 (29%) at relapse (P = 0.002). PgR expression was likewise significantly reduced in this group (P = 0.001). This study confirms that expression of a functional ER in breast cancer is a strong predictor for primary response to tamoxifen. Although ER was reduced in tamoxifen-resistant tumors overall, the development of acquired resistance was associated with maintained ER expression and function in many tumors, whereas de novo resistance remained related to lack of ER expression. Recurrence during adjuvant tamoxifen was associated with development of an ER/PgR-negative phenotype in some tumors. These data imply that separate mechanisms of resistance may occur in these different clinical subgroups.

HER-2 amplification impedes the antiproliferative effects of hormone therapy in estrogen receptor-positive primary breast cancer.

In experimental models, human epidermal growth factor receptor-2 (HER-2) amplification leads to estrogen independence and tamoxifen resistance in estrogen receptor (ER)-positive human breast cancer cells. Some but not all reports suggest an association between HER-2 positivity and hormone independence in breast cancer patients. This study aimed to evaluate the antiproliferative effects of endocrine therapy in HER-2-positive/ER-positive primary human breast cancer. The effect on proliferation (Ki67) of hormone therapy was assessed at 2 weeks and/or 12 weeks in biopsies from 115 primary breast cancers with ER-positive tumors. The patients took part in one of 3 neoadjuvant trials of hormonal therapy with a SERM (tamoxifen or idoxifene) or an aromatase inhibitor (anastrozole or vorozole). HER-2 status was assessed by immunocytochemistry and fluorescence in situ hybridization (FISH). Fifteen patients were defined as HER-2 positive by both immunohistochemistry and FISH, with the remaining 100 patients HER-2 negative. Geometric mean Ki67 levels were substantially higher in HER-2-positive than HER-2-negative tumors (27.7% versus 11.5%, respectively; P = 0.003). In HER-2-negative patients, Ki67 was reduced by 62 and 71% at 2 and 12 weeks, respectively (P < 0.0001 for both), but HER-2-positive patients showed no significant fall. The proportional change in Ki67 was significantly different between HER-2-positive and -negative patients (P = 0.014 at 2 weeks; P = 0.047 at 12 weeks). Mean ER levels were lower in the HER-2-positive patients (P = 0.06) but the change in Ki67 was impeded even in those with high ER. Apoptotic index was reduced by 30% at 2 weeks in the HER-2-negative group. However, there were no statistically significant differences in apoptotic index between the groups. It is concluded that ER-positive/HER-2-positive primary breast carcinomas show an impeded antiproliferative response to endocrine therapy that nonetheless may vary between individual treatments. This together with high baseline proliferation is likely to translate to poor clinical response.

Clinical prognostic and predictive factors for primary chemotherapy in operable breast cancer.

PURPOSE: This study aimed to identify clinical factors that are of prognostic significance or that predict for subsequent treatment outcome in patients with large operable breast cancer treated with primary chemotherapy (PCT) at our institution. METHODS: One hundred eighty-five patients received the following regimens: CMF or MMM (76 patients), ECF (75 patients), AC or FEC (34 patients), followed by surgery, with radiotherapy (RT) given to those with breast conservation. A number of common clinical variables were assessed in relation to local recurrence-free survival (LRFS), disease-free survival (DFS), and overall survival (OS). RESULTS: Clinical responders had improved DFS (P = .009) and OS (P = .08) compared with nonresponders. There was no association between clinical or pathologic complete remission (CR) and survival. Pretreatment clinical axillary node positivity was a significant predictor of worsened DFS (P = .0001), OS (P = .0001), and LRFS (P = .03). Patients remaining clinically node-positive postchemotherapy had an inferior outcome compared with those becoming node-negative (DFS, P = .03; OS, P = .03) but pathologic axillary node status was not shown to predict for survival. Twenty-nine patients in clinical CR following PCT who electively did not have surgery and were treated with RT alone had significantly increased local recurrence rate compared with partial responders having surgery and RT (P = .02). There were no differences in DFS or OS between these groups. On multivariate analysis, clinical axillary node status was the only independent predictor of OS and DFS, and LRFS. CONCLUSION: Pretreatment and posttreatment clinical axillary node status is a major predictor of outcome following PCT. Complete clinical response does not define a more favorable subgroup compared with those not obtaining CR.

High complete remission rates with primary neoadjuvant infusional chemotherapy for large early breast cancer.

PURPOSE: To investigate the efficacy of continuous infusion fluorouracil (5FU) with every-3-week epirubicin and cisplatin (ECF) as primary chemotherapy instead of immediate mastectomy for patients with large, potentially operable, breast cancer. PATIENTS AND METHODS: Fifty patients with large operable breast cancer, median tumor diameter 6 cm (range, 3 to 12), were treated with 5FU 200 mg/m2/d via a Hickman line using an ambulatory pump for 6 months with epirubicin 50 mg/m2 intravenously (IV) and cisplatin 60 mg/m2 IV every 3 weeks for eight courses. Subsequent surgery and/or radiotherapy was determined by clinical response. RESULTS: Forty-nine patients achieved an overall response (98%; 95% confidence interval [CI], 94% to 100%), including 33 complete clinical remissions (CRs) (66%; 95% CI, 53% to 79%). Only three patients (6%) still required mastectomy. Tumor cellularity was markedly reduced on repeat needle biopsy following 3 weeks of treatment in 81% of patients versus only 36% in similar patients after conventional chemotherapy (P < .002). Severe (World Health Organization [WHO] grade 3 to 4) toxicity was rare, with nausea/vomiting being the most common, occurring in 20% of patients. CONCLUSION: Primary infusional ECF appears to be more active on clinical and histopathologic grounds than conventional chemotherapy for large operable breast cancer and is well tolerated. This approach now merits randomized comparison to determine if high CR rates may translate into improved survival.

Is surgery necessary after complete clinical remission following neoadjuvant chemotherapy for early breast cancer?

PURPOSE: This retrospective analysis aimed to identify whether breast cancer patients receiving radiotherapy alone following a complete clinical remission (cCR) to neoadjuvant chemotherapy had a worse outcome than those treated with surgery. PATIENTS AND METHODS: One hundred thirty-six patients who had achieved a cCR to neoadjuvant chemotherapy for early breast cancer were identified from a prospectively maintained database of 453 patients. Of these, 67 patients had undergone surgery as their primary locoregional therapy, and 69 patients had radiotherapy alone. Outcome was assessed in relation to local recurrence-free survival, disease-free survival, and overall survival. RESULTS: Median follow-up was 63 months in the surgery group and 87 months in the no surgery group. Prognostic characteristics were well balanced between the two groups. For surgery and no surgery, respectively, there were no significant differences in disease-free survival or overall survival (5-year, 74% v 76%; 10-year, 60% v 70%, P =.9) between the two groups. There was a nonsignificant trend toward increased locoregional-only recurrence for the no surgery group (21% v 10% at 5 years; P =.09), but no long-term failures of local control. Patients in the no surgery group who also achieved an ultrasound complete remission had a 5-year local recurrence rate of only 8%. CONCLUSION: In patients achieving a cCR to neoadjuvant chemotherapy, radiotherapy alone achieve survival rates as good as with surgery, but with higher local recurrence rates. Ultrasound may identify a low recurrence rate subgroup for assessing no surgery in a prospective trial.

Does genetic counseling have any impact on management of breast cancer risk?

Despite there being an increasing literature on the impact of cancer genetic counseling on risk perception and mental health, there is a lack of data describing impact on risk management. Genetic counseling and testing for cancer predisposition genes aims to improve the future health of those at high risk through appropriate surveillance and screening. However, management of breast cancer risk in women with a family history of this disease is an area of controversy. Counseling services may recommend specific risk management options to women, who then rely on their local screening service to make provision. This study investigated the impact of genetic counseling on management of breast cancer risk in women attending Cancer Family Clinics. A total of 293 women attending four genetic clinics were enrolled. Rates of breast self-examination, clinical breast examination, mammography, biopsy, detected cancers, and other screenings were documented. Participants' perceived benefits and barriers to mammography were assessed along with cancer worry. Results show that rates of mammography, clinical breast examination, and breast self-examination were increased following clinic attendance (p < 0.001). Women in the under 35 age-group had limited access to screening. Rates for biopsy and detected cancers were low. Women reported positive attitudes to mammography, with few reported barriers. Contrary to previous studies, there was no evidence that anxiety about breast cancer impedes uptake of health surveillance methods. Genetic counseling had a positive impact on management of breast cancer risk. Whether this translates into future health gains remains to be established.

Matching supraclavicular fields to the extent of axillary surgery in women prescribed radiotherapy for early stage carcinoma of the breast.

AIMS: To determine (1) if the lower border of a standard anterior radiotherapy field to the supraclavicular fossa matches the upper limit of level II/III axillary dissection; and (2) whether standard lung blocks in patients prescribed axillary radiotherapy shield target axillary tissue in women with breast cancer. MATERIALS AND METHODS: Between 1999 and 2001, 30 women with breast cancer undergoing level II/III axillary dissection had titanium clips placed to define the upper and medial limits of surgery. At radiotherapy planning, a supraclavicular fossa field similar to that described in the UK START trial protocol was simulated, with head twist applied to position the inferior field border (50% isodose) 1 cm below and parallel to the lower border of the clavicle. The field position was recorded on X-ray film. The location of the most superior axillary clip was measured in relation to this inferior field border on the X-ray film. The location of the most medial clip was measured in relation to the lung/chest wall interface. RESULTS: The median distance between the most superior clip and the inferior border of the supraclavicular field was 3.6 cm (0.8-6.9 cm), representing significant underlap in all cases. In addition, five out of 30 (17%) patients had surgical clips over 2.0 cm medial to the lung/chest wall interface, suggesting that medial lymph nodes in an undissected axilla would be shielded by standard lung blocks in patients prescribed axillary radiotherapy. CONCLUSION: Current standard radiation fields to the supraclavicular fossa, as applied in this study, leave apical axillary lymph nodes untreated in a high proportion of patients. Standard lung shielding, as applied in this study to patients simulated for axillary radiotherapy, protect medial axillary lymph nodes in a few patients. A change in practice is recommended.

Sentinel node biopsy should be supplemented by axillary sampling in patients with small breast cancers.

Axillary clearance provides important prognostic information but is associated with significant morbidity. Sentinel node biopsy can provide staging .141 patients with node negative early breast cancers-tumour size less than 1.5 cm measured clinically or by imaging had guided axillary sampling (sentinel lymph node biopsy in combination with axillary sampling). Four node axillary sampling improved the detection rate of axillary node metastases by 13.6% as compared to blue dye sentinel node biopsy alone. Positive sampled nodes strongly indicated the likelihood of further metastatic being revealed by axillary dissection (67%). Negative sampled nodes in combination with a positive sentinel node biopsy were associated with a much lower rate of further nodal involvement in the axillary clearance (8%).

Evolution of Renal Transplant Practice Over the Past Decade: A U.K. Center Experience.

OBJECTIVE: As renal transplantation continues to evolve, there appears to be a change in both donor and recipient populations. Traditional markers of high-risk donor (e.g. donation after cardiac death [DCD]/expanded criteria donor [ECD]) and recipient (e.g. obese, highly sensitized) operations appear to be more common without any noticeable worsening of patient outcome. The present study aimed to compare outcome and define the change in donor and recipient populations for cadaveric transplants over a 10-year period at a large U.K. center. METHODS: Single-center analysis of all adult patients undergoing cadaveric renal transplantation between January 2004 and January 2014 (n = 754). Transplants were divided into 3 groups (early, middle, and late) depending on the era, with donor, recipient and outcomes compared. RESULTS: There were considerable changes in both donor and recipient factors between the 3 eras, with a greater proportion of high-risk operations performed, as reflected by significant increases in Donor Risk Index (median: 1.11-1.16, P = .022), and the proportions of ECD (22.2%-33.9%, P = .003) and DCD kidneys (10.8%-19.4% P = .011). However, 1-year graft survival was comparable between the eras, with a decrease in the average 1-year serum creatinine between the early and late cohort (median: 161 µmol/L vs 132 µmol/L, P < .001). There was no significant increase in body mass index (BMI) in either the donor or recipient population across the eras. CONCLUSION: Improvement in transplant outcome continues despite a greater proportion of transplants previously considered as high risk being performed. This is likely to reflect a considerable improvement in pre- and postoperative management. BMI remains a major continuing block to transplantation.

Desmoid tumours treated with triphenylethylenes.

Desmoids are uncommon mesenchymal tumours that occur at single or multiple anatomical sites, occasionally in association with polyposis coli. This paper describes the use of the triphenylethylene tamoxifen, and a new chlorinated analogue, toremifene, in 20 patients with progressive desmoid disease. Clinical responses ranging from stabilisation of disease to complete resolution were observed in 65% of cases. The antitumour activity of this group of drugs has been attributed to their anti-oestrogenic behaviour. However, desmoids provide a clinical model of a purely mesenchymal tumour which appears to respond despite having generally low levels of hormone receptor. This emphasises the significance of stroma within breast (and other) tumours, in particular how the stroma may regulate the response to these drugs regardless of receptor status.

Side-effects of screening.

There has been a 42% increase in the number of mammograms performed outside the national screening programme (operating in Camberwell, southeast London) which was not anticipated in the Forrest Report, a document to the Health Ministers of the U.K. by a working group chaired by Sir Patrick Forrest. The report compiles recommendations on breast screening, using mammography and breast self-examination, to reduce the mortality in women aged 50-64 years. This 42% increase is attributable mainly to referrals from menopause clinics and general practitioners of patients mainly in the screening age group. When we looked at referrals from general practitioners, suspicious mammographic findings were reported in 20% of patients referred with a breast lump, in contrast to only 4% of patients referred with breast pain or nodularity. Better education of both the public and general practitioners, concerning the signs and symptoms of breast cancer, may reduce demands to perform mammographies outside the current national screening programme.

Lymphatic relapse in women with early breast cancer: a difficult management problem.

The aim of this study was to review the ability to control symptoms of regional lymphatic relapse in women with early breast cancer. A retrospective study was made of 759 consecutive women presenting with stage 1 or 2 breast cancer treated by breast conserving surgery and radiotherapy between June 1984 and December 1994, 291 (38.3%) of whom were managed by a policy of observation on the lymphatic pathways. Patterns of lymphatic relapse, relapse management and morbidity caused by recurrent malignancy were reviewed from the case notes. The overall rate of relapse in the ipsilateral axilla and/or supraclavicular fossa was 76/759 (10%) at any time prior to death or last follow-up. 34 of 65 patients who relapsed in the axilla did so despite prior axillary surgery and/or radiotherapy. 41 of 76 patients with regional recurrence presented with symptoms, including lymphoedema, arm pain or sensory motor changes. These symptoms were poorly controlled by palliative surgery, radiotherapy or systemic therapy in 23 cases, including 12 who progressed to arm paralysis. Symptomatic control of patients with regional lymphatic relapse can be very difficult, even in women under regular surveillance in a multidisciplinary breast cancer clinic.

Selective avoidance of lymphatic radiotherapy in the conservative management of women with early breast cancer.

BACKGROUND AND PURPOSE: Until recently, elective treatment of the lymphatic pathways in women with early invasive breast cancer was assumed to impact on quality of life rather than on overall survival. In a multidisciplinary breast clinic these considerations underpinned a policy of observation of the lymphatic pathways if axillary lymph nodes were not palpably enlarged and if recommendations for adjuvant systemic therapy did not depend on knowledge of pathological node status. This paper evaluates the long-term outcome of the observation policy in terms of lymphatic morbidity due to cancer recurrence. MATERIAL AND METHODS: Seven hundred and fifty-nine patients with operable breast cancer and suitable for breast conserving surgery were seen between January 1984 and December 1994. Of these, 291 (38.3%) were recommended a policy of observation to the lymphatic pathways. The case records of these patients were reviewed to record regional relapse patterns and morbidity. RESULTS: At a median follow up of 60 months, 32/291 (11%) patients suffered ipsilateral lymphatic relapse at some stage prior to death or last follow up, representing a 22% actuarial 10-year risk of lymphatic relapse. Metastases coincided with, or preceded, lymphatic relapse in 8/32 (25%) patients. Eighteen out of 32 (56%) patients suffered symptoms of lymphatic relapse prior to death or last follow up, despite subsequent surgery, radiotherapy and/or systemic therapies. The absolute risk of symptomatic ipsilateral lymphatic relapse in the observation group was 18/291 (6.2%), representing an actuarial 10-year risk of 17%. CONCLUSION: A policy of observation on the axilla with deferred treatment of lymphatic relapse has benefited 273/291 (94%) patients, but at the expense of cancer-related regional morbidity in 18 (6%) patients. We conclude that the cancer-related morbidity suffered by a minority of patients and the strengthening evidence of an overall survival benefit conferred by elective local-regional therapy favours a policy of elective treatment of the lymphatic pathways in the routine setting.

Selective avoidance of lymphatic radiotherapy in the conservative management of early breast cancer.

In view of the morbidity and potential mortality associated with routine post-operative lymph node radiotherapy in women with early stage breast cancer, an attempt has been made to select patients in whom radiotherapy can be withheld. Three hundred and forty-seven consecutive patients treated wide local excision plus or minus axillary surgery have been evaluated. Only 20% were subsequently given radiotherapy to regional nodes. Relapse in the axilla, the supraclavicular fossa or at both these sites have occurred in 16 patients so far, 12 of whom were successfully treated. Systemic relapse was seen in eight of these patients occurring with one exception before or within 3 months of node relapse. Only four have persisting symptoms as a result of nodal relapse. So far, a policy involving selective lymphatic radiotherapy in women treated for early breast cancer appears justified.

Seroma following breast cancer surgery.

BACKGROUND: Seroma is a common problem following breast cancer surgery causing patient discomfort and prolongation of hospital stay. METHODS: This manuscript reviews the relevant literature obtained by an extensive search of the medline database. In addition papers were also derived from the reference lists of retrieved articles. RESULTS AND CONCLUSION: The advantages and disadvantages of the various methods to deal with seroma are discussed. Based on this an individual patient based policy can be formulated.

Prospective evaluation of a low maintenance policy for semipermanent silicone vascular access catheters.

Twenty-six women had semipermanent vascular access catheters (VACs) inserted to allow weekly outpatient infusion chemotherapy for advanced breast cancer. VACs were maintained without occlusive dressings, antibiotics, repeated flushings or heparin for a total of 2294 patient days (range 6 to 217 days, median 55 days). Three exit site and one subcutaneous tunnel infection occurred but no patient suffered septicaemia. VACs allowed both blood sampling and drug administration on 267 occasions and drug administration only on 19 occasions. No catheter became completely occluded.

Trial of aminoglutethimide vs hydrocortisone as second-line hormone treatment of advanced breast cancer.

In a randomized trial of second line hormone therapy 56 postmenopausal women with advanced breast cancer received low dose aminoglutethimide (AGT) 125 mg twice daily without hydrocortisone (27 patients), or hydrocortisone (HC) 20 mg twice daily (29 patients). The two groups were well-matched for previous response to tamoxifen (TAM) therapy (AGT (35%) vs HC (32%)) and for relapse on adjuvant TAM. The mean age of the two groups was 69.2 years (AGT) and 63.2 years (HC). Liver metastases were present in 29% (AGT) and 33% (HC). The response rates were 11% (AGT) and 21% (HC). At 12 months the failure of treatment rate was 80% (AGT) and 70% (HC). Survival at 12 months was 50% for both groups. At 12 months 5/12 survivors were still on AGT and 8/12 on HC. These preliminary findings have so far failed to show any statistical difference in tumour response, time to treatment failure or survival between low-dose AGT and HC as second-line hormone treatment post-tamoxifen in advanced breast cancer.