Chemotherapy For Primary Breast Cancer Research Articles

A nonreplicating adenoviral vector that contains the wild‐type p53 transgene combined with chemotherapy for primary breast cancer

: Primary systemic therapy (PST) is the standard approach to the management of patients with locally advanced breast cancer (LABC). The authors hypothesized that the intratumoral administration of a nonreplicating adenoviral vector (Ad5) that contains the human wild-type p53, AdCMV-p53, combined with chemotherapy, could increase the efficacy of PST as measured by pathologic complete response. : In a prospective, open-label, Phase II trial, 13 patients with LABC were treated with 6 3-week cycles of PST, which consisted of intratumoral injections of Ad5CMV-p53 for 2 consecutive days plus docetaxel and doxorubicin followed by surgery. p53 status was determined at baseline and was assessed immediately after the first injection (up to 48 hours). Clinical response was assessed by clinical and radiologic methods. : The trial was terminated early, because none of the patients achieved a pathologic complete response. The median age was 56 years (range, 39-71 years), and the median tumor size was 8 cm (range, 5-11 cm). Eight patients (73%) had a p53 mutation. Serial biopsies showed an increase in p53 messenger RNA (mRNA) and p21(WAF1/Cip1) mRNA. All 12 evaluable patients achieved an objective clinical response. The surgical specimens revealed scattered tumor cells with extensive tumor-infiltrate leukocytes (predominantly T-lymphocytes). At a median follow-up of 37 months (range, 30-41 months), 4 patients (30%) developed systemic recurrence, and 2 patients died. The estimate breast cancer-specific survival rate at 3 years was 84% (95% confidence interval, 65.7-100%). There was no increase in systemic toxicity. : Ad5CMV-p53 combined with PST is safe, active, and associated with local immunomodulatory effects. The promising clinical activity of this combination deserves further investigation in randomized studies.

Changes in thymidine phosphorylase expression in response to neoadjuvant chemotherapy for primary breast cancer

655 Background: Thymidine phosphorilase (TP) is a key enzyme involved in nucleoside metabolism. Recently, it has been hypothesized that TP modulation could enhance the therapeutic activity of TP-targeting chemotherapy such as capecitabine. In addition, some evidence exists that anticancer agents could upregulate TP. The present study analyzed TP immunohistochemical expression in response to neoadjuvant chemotherapy for primary breast cancer. Methods: Fifty-five women with operable breast cancer (T ≥ 2 cm, N0–1, M0) were treated with anthracycline-based (all cases) and anthracycline/taxane-based (n= 40 cases) neoadjuvant chemotherapy. Tumor samples from diagnostic large core biopsy (n=55) and from surgery (n=53) were available for histological evaluation and immunohistochemical analysis of TP. Immunohistochemistry was performed at a single central laboratory using a primary mouse anti-TP monoclonal antibody (Roche molecular biochemicals).TP expression was evaluated on tumor cells (nuclear and cytoplasmic staining) and on stromal cells. The intensity of cytoplasmic immunoreactivity was scored as 0, 1, 2 or 3 denoting negative, weak, moderate and strong staining, respectively. Results: An increase in TP cytoplasmic expression was observed in 35.89% (95% CI: 0.21–0.52%) of tumor samples after neoadjuvant chemotherapy. In particular, increases in cytoplasmic TP score were more common after taxane-containing regimens (40.74%, 95% CI: 0.22–0.61%) than after regimens without taxanes (25%, 95% CI: 0.05–0.57%). No significant changes of TP expression were found in nuclei of tumor cells after neoadjuvant chemotherapy. Similarly, no significant changes of TP expression were observed in stromal cells. There was no significant association between clinical or pathological response rate and TP changes in both tumor and stromal cells. Conclusions: This study provides further evidence that, at least in breast cancer, TP is upregulated after anthracycline and/or taxane-containing chemotherapy. According to these results, a strong rationale exists in combining TP-inducing and TP-targeting anticancer agents. No significant financial relationships to disclose.

Clinical response assessment after 2 cycles of neoadjuvant chemotherapy for primary breast cancer fails to predict for final clinical response, but does predict for pathological complete response

667 Background: Neoadjuvant chemotherapy (NC) is increasingly being used for large primary breast carcinomas. Clinical trials have established its role in improving breast-conserving surgery (BCS) rates and have shown that complete pathological response (pCR) is associated with improved survival. Early evaluation of response is important for selecting patients with possible worse outcomes, who may benefit from alternative treatments. Methods: 107 women received NC for large operable breast cancers (T2–4, N1–2, M0). Patients received 6 cycles of FEC chemotherapy (5-FU 500mg/m2, epirubicin 75mg/m2, cyclophosphamide 500mg/m2 every 21 days) prior to a planned operation. Clinical response was recorded at baseline, after 2 cycles of NC and on completion of 6 cycles. Baseline and completion ultrasound and/or mammography were performed and a pathological assessment of response was made in those patients who underwent surgery. Results: Median age was 50 (range= 29–78). Overall clinical response rate after 2 cycles of chemotherapy was 59.8% (64/107) and after 6 cycles was 84.1% (90/107). 56 patients (52.3%) underwent BCS, 37 (34.6%) mastectomy and 14 (13.1%) no operation. Overall pCR rate was 15.0% (16/107). Of the 43 patients who failed to respond clinically after 2 cycles, 27 (62.8%) went on to exhibit a clinical response on completion of chemotherapy. 3 (7.0%) patients went on to have a complete clinical response and 21 (48.8%) underwent BCS. However, none of these 43 patients demonstrated a pCR. Conclusions: Lack of clinical response after 2 cycles of neoadjuvant chemotherapy does not preclude clinical response after further treatment with the same schedule, and many women will have sufficient down-staging to enable breast-conserving surgery. However, a pathological complete response is unlikely if no clinical response is observed after 2 cycles. No significant financial relationships to disclose.

Apoptotic disseminated tumor cells reflect response to primary chemotherapy in breast cancer

654 Background: Primary chemotherapy (pCHT) is an established method to reduce tumor size (downstaging) in breast cancer patients before performing breast conserving therapy. The consequences of pCHT on tumor cell dissemination in these patients are not known. The aim of this study was to investigate (1) the incidence of disseminated tumor cells (DTC) including apoptotic DTC in patients with breast cancer after primary chemotherapy and (2) its correlation with pathological therapy response. Methods: Bone marrow aspiration was performed in 157 patients after primary chemotherapy. Cytokeratin-positive cells were detected by immunocytochemistry using the AB45-B/B3 anti-cytokeratin antibody. For detection of apoptotic tumor cells the antibody M30 (Roche Diagnostics, Germany) was used. M30 reacts with a neo-epitope expressed only after caspase cleavage of CK 18 during early apoptosis. Results: The incidence of disseminated tumor cells in breast cancer patients was 57% (84 of 157 pts) after completion of primary systemic therapy. Tumor dissemination was observed more frequently in patients with no change/progressive disease (NC+PD: 63%) than in those who showed partial (PR) or complete remission (CR) of the primary tumor (PR+CR: 43%) (p<0.05). However, 9 of 23 (40%) patients with complete response were still bone marrow positive. Apoptotic tumor cells were present in 36 of 157 (23%) breast cancer patients. The positivity rate of apoptotic cells was higher in bone marrow positive patients with PR or CR (42%) compared to those with stable disease (SD) (26%). No apoptotic tumor cells were detected in patients with tumor progression (n=5). Conclusions: The pathological therapy response is reflected by the presence of apoptotic tumor cells in the bone marrow of breast cancer patients. However, patients with complete response may still have non apoptotic disseminated tumor cells. Patients with tumor cell dissemination after primary systemic therapy may be benefit from additional secondary adjuvant treatment (e.g. bisphosphonates, antibody based strategies). No significant financial relationships to disclose.

Primary chemotherapy in breast cancer shows excellent clinical and pathological response with docetaxel and epirubicin

10779 Background: Primary chemotherapy is becoming the standard of care for locally advanced breast cancer. Recently tested regimens using new drugs have been showing better results than usual anthracycline based treatments. Methods: From April 1998 through April 2004, 104 patients (18 stage IIA; 36 stage IIB; 13 stage IIIA; 33 stage IIIB; 4 stage IV) were included in the trial and received three cycles of docetaxel 75 mg/m2 and epirubicin 50 mg/m2 (q3w). Patients with stable or progressive disease were excluded from the trial, receiving alternative treatment. Those with partial response after three cycles but still not suitable for conservative surgery received up to 3 additional cycles. Following completion of the chemotherapy regimen, tumour response was assessed and appropriate surgery performed. Pathological response was evaluated in excised specimens. Results: According to the UICC criteria for clinical evaluation, 79 pts (76%) had objective regression (14 CR and 65 PR); 21 resulted in stabilised disease and 4 showed progression (24%). There was no toxicity in 62 patients, grade I/II in 4 and grade III/IV in seven patient. Ninity-nine patients became eligible for surgery (95%); 60 underwent conservative surgical treatment (60.6%) and in 39 patients a modified radical surgery was done (39.4%). No axyllary involvement were detected in 22 patients, other 23 had 1–3 positive nodes and 54 had 3 or more positives node in axillary dissection. 338 chemotherapy cycles were given, with an average of previously expected 3.25 cycles per patient. Conclusions: Our study demonstrates a high response rate with primary docetaxel and epirubicin chemotherapy in locally advanced breast cancer and high axillary envolvement group, enabling conservative surgery to take place and carrying no significant toxicity. Survival rate was directly linked to pathological response and complete response was associated to highest rate of survival in the group. No significant financial relationships to disclose.

Evaluation of Ki-67 proliferation and apoptotic index before, during and after neoadjuvant chemotherapy for primary breast cancer

IntroductionBiological markers that reliably predict clinical or pathological response to primary systemic therapy early during a course of chemotherapy may have considerable clinical potential. This study evaluated changes in Ki-67 labeling index and apoptotic index (AI) before, during, and after neoadjuvant anthracycline chemotherapy.MethodsTwenty-seven patients receiving neoadjuvant FEC (5-fluorouracil, epirubicin, and cyclophosphamide) chemotherapy for operable breast cancer underwent repeat core biopsy after 21 days of treatment. Tissue from pre-treatment biopsy, day 21 and surgery was analysed for Ki-67 index and AI.ResultsThe objective clinical response rate was 56%. Eight patients (31%) achieved a pathological response by histological criteria; two patients had a near-complete pathological response. A reduction in Ki-67 index was observed in 68% of patients at day 21 and 72% at surgery; Ki-67 index increased between day 21 and surgery in 54%. AI decreased in 50% of tumours by day 21, increased in 45% and was unchanged in one patient; 56% demonstrated rebound increases in AI by the time of surgery. Neither pre-treatment nor post-chemotherapy median Ki-67 index nor median AI at all three time points or relative changes at day 21 and surgery differed significantly between clinical or pathological responders and non-responders. Clinical responders had lower median Ki-67 indices at day 21 (11.4% versus 27.0%, p = 0.02) and significantly greater percentage reductions in Ki-67 at day 21 than did non-responders (-50.6% versus -5.3%, p = 0.04). The median day-21 Ki-67 was higher in pathological responders (30.3% versus 14.1%, p = 0.046). A trend toward increased AI at day 21 in pathological responders was observed (5.30 versus 1.68, p = 0.12). Increased day-21 AI was a statistically significant predictor of pathological response (p = 0.049). A strong trend for predicting pathological response was seen with higher Ki-67 indices at day 21 and AI at surgery (p = 0.06 and 0.06, respectively).ConclusionThe clinical utility of early changes in biological marker expression during chemotherapy remains unclear. Until further prospectively validated evidence confirming the reliability of predictive markers is available, clinical decision-making should not be based upon individual biological tumour marker profiles.

Association between Immunohistochemical Expression of Topoisomerase IIα, Her2 and Hormone Receptors and Response to Primary Chemotherapy in Breast Cancer

The aim of this study was to evaluate the association between immunohistochemical expression of topoisomerase IIalpha, HER2 and hormone receptors and response to primary anthracycline-based chemotherapy in locally advanced breast cancer. We analyzed 109 medical charts of patients treated with primary anthracycline-based chemotherapy in the Women's Integral Health Care Center from 1996 to 2004. The clinical and pathological response to primary chemotherapy was associated with topoisomerase Ilalpha and HER2 expression and hormone receptor negativity. Statistical analysis was performed using chi-squared, Fisher's exact test and Mann-Whitney test. No statistical association between clinical response and expression of topoisomerase Ilalpha, HER2 and hormone receptor negativity was found. However, there was an association between complete pathological response and hormone receptor negativity (P = 0.0289). The present study suggested that these markers should not be considered predictors of response to primary anthracycline-based chemotherapy, and prospective studies must be designed for this purpose.

Evaluation of HER-2/Neu Amplification and Other Biological Markers as Predictors of Response to Neoadjuvant Anthracycline-Based Chemotherapy in Primary Breast Cancer

The value of HER-2/neu status as a predictor of response to anthracycline-based chemotherapy is still a matter of debate. We evaluated the contribution of HER-2/neu gene amplification and other biologic markers in predicting response to different doses of neoadjuvant anthracycline-based chemotherapy. Clinical and pathologic records of 115 primary breast cancer patients were reviewed. Forty-eight and 67 patients received high (doxorubicin > or =20 mg/m2/wk; epirubicin > or =30 mg/m2/wk) and moderate-low anthracycline dose intensity regimens, respectively. Pathologic diagnosis, hormonal receptor status (HR), Ki67, and HER-2/neu status were assessed on tumor samples before neoadjuvant chemotherapy. HER-2/neu was determined by fluorescence in situ hybridization (FISH). HER-2/neu amplification was observed in 29/115 (25%) tumors, 18 from moderate-low-dose and 11 from high-dose group. In the univariate analysis, a high Ki67 index (> or =20%) and positive clinical axillary nodes were predictive of an objective tumor response (P = 0.033 and 0.001, respectively). In the multivariate analysis, Ki67 was the only factor predictive of response (OR = 3.08, 95% CI = 1.1-8.5, P = 0.03). HER-2/neu status was not a factor in predicting objective response to different anthracycline dose intensities. The same finding was observed with regards to HR and Ki67. In our series, no significant dose-response relationship was found according to HER-2/neu status.

Circulating endothelial cells and angiogenic serum factors during neoadjuvant chemotherapy of primary breast cancer

Circulating endothelial cells (CECs) as well as bone-marrow-derived endothelial precursor cells (EPC) play an important role in neovascularisation and tumour growth. To study the impact of neoadjuvant chemotherapy on the amounts of CEC and their precursor cells, mature CEC and their progenitors were quantified by flow cytometry in peripheral blood of breast cancer patients during anthracycline and/or taxane based neoadjuvant chemotherapy and subsequent surgery in comparison to age-matched healthy controls. Cell numbers were tested for correlation with serum levels of angiopoietin-2, erythropoietin, endostatin, endoglin, VEGF and sVCAM-1 as well as clinical and pathological features of breast cancer disease. Circulating endothelial cells were significantly elevated in breast cancer patients and decreased during chemotherapy, whereas EPC (CD34+/VEGFR-2+) as well as their progenitor cell population CD133+/CD34+ and the population of CD34+ stem cells increased. Concomitantly with the increase of progenitor cells an increase of VEGF, erythropoietin and angiopoietin-2 was observed. These data suggest that chemotherapy can only reduce the amounts of mature CEC, probably reflecting detached cells from tumour vessels, whereas the EPC and their progenitors are mobilised by chemotherapy. Since this mobilisation of EPC may contribute to tumour neovascularisation an early antiangiogenic therapy in combination with chemotherapy could be beneficial for the success of cancer therapy.

P53 Codon 72 Polymorphism Predicts the Pathologic Response to Neoadjuvant Chemotherapy in Patients with Breast Cancer

Recent studies have highlighted that the p53 codon 72 polymorphism plays a crucial role in modulating wild-type p53 apoptotic capacity, and as such may influence the response to chemotherapy. Thus, the purpose of this study was to investigate whether the p53 codon 72 polymorphism might influence pathologic response to neoadjuvant chemotherapy in primary breast cancer. One hundred and ten operable breast cancer patients received anthracycline-based neoadjuvant chemotherapy and p53 codon 72 polymorphism status was analyzed by PCR-RFLP. The distribution of initial clinical stage, tumor size, estrogen receptor or progesterone receptor status, menopausal status, or erbB2 expression was not significantly different among the polymorphic variants. However, we found that only 13% (3 of 23) of patients with the Pro/Pro variant had a good pathologic response, defined as a complete pathologic response or minimal residual disease. In comparison, 40% (22 of 55) or 37.5% (12 of 32) of patients with the Pro/Arg or Arg/Arg variant had a good pathologic response (P = 0.019). Moreover, patients with the Pro/Pro variant were more likely to have a positive axillary lymph node status than those with the Pro/Arg or Arg/Arg variant (P = 0.007). Furthermore, in multivariate analysis, p53 codon 72 polymorphism was found to be a strong predictor of pathologic response (odds ratio 6.7, 95% confidence interval, 1.4-31.2; P = 0.016). Our study indicates that breast cancer patients with the Pro/Pro variant may be less sensitive to anthracycline-based treatment than those with the Pro/Arg or Arg/Arg variant and suggests that analysis of p53 codon 72 polymorphism may provide a simple predictive marker for selecting the right breast cancer patients to anthracycline-based neoadjuvant chemotherapy in clinical setting.

293 POSTER Gene expression associated to response to doxorubicin based primary chemotherapy in breast cancer

293 POSTER Gene expression associated to response to doxorubicin based primary chemotherapy in breast cancer

‘Small’ randomised neo-adjuvant chemotherapy trials in breast cancer reporting on pathological response: more harm than good?

‘Small’ randomised neo-adjuvant chemotherapy trials in breast cancer reporting on pathological response: more harm than good?

Serum levels of IGF-1 and IGFBP-3 during adjuvant chemotherapy for primary breast cancer

High serum concentrations of insulin-like growth factor-1 (IGF-1) are associated with an increased risk of breast, prostate, colorectal, and lung cancer whereas IGF binding protein-3 (IGFBP-3) seems to exert a protective effect. Therefore, patients may benefit from low IGF-1 levels and high IGFBP-3 levels. This study evaluated whether adjuvant anthracycline-containing chemotherapy modulates IGF-1 and/or IGFBP-3 serum levels in breast cancer patients. In 18 patients undergoing adjuvant treatment for primary breast cancer, IGF-1 and IGFBP-3 serum levels were measured with immunoassays during chemotherapy regimens of either 5-fluorouracil, epirubicin and cyclophosphamide (FEC) or epirubicin and cyclophosphamide (EC). Mean pre-treatment values of IGF-1 and IGFBP-3 were 124+/-13 and 3698+/-186 ng/ml, respectively. No significant changes in IGF-1 and IGFBP-3 serum concentrations were observed during adjuvant anthracycline-containing chemotherapy. IGF-1 levels significantly correlated with IGFBP-3 levels before and during chemotherapy. In conclusion, these chemotherapy regimens do not seem to modulate IGF-1 or IGFBP-3 levels in a favourable or unfavourable way.

Evaluation of tumour microvessel density & pericyte coverage index following neoadjuvant chemotherapy in primary breast cancer

655 Background: Angiogenesis is critical for the growth & metastasis of breast tumours & can be quantified using intratumoural microvessel density (MVD). Pericyte recruitment to the tumour microvasculature is thought to reflect vessel maturation & thus pericyte coverage index (PCI) provides a qualitative measure of tumour angiogenesis. Here we assess the effect of anthracycline-based neoadjuvant chemotherapy (NAC) on MVD & PCI in primary breast cancer (PBC). Methods: Paired pre- & post-treatment pathological specimens (diagnostic core biopsy & definitive surgical resection specimen respectively) from 80 women with PBC (median age 47 years; range 29 - 70) who received 5-fluorouracil, epirubicin & cyclophosphamide (FEC) NAC were analysed. Immunohistochemical double-staining was performed using the panendothelial marker, CD34, & alpha-smooth muscle actin (α -SMA). MVD & PCI were scored from random fields (median 9; range 2–31) at x200 magnification or, in the case of small samples (n=20), from all fields (median 2; range 1–12). Individual microvessels (CD34 positive) were counted per field & expressed per mm2. PCI was scored as the number of CD34 & α -SMA positive vessels & expressed as a percentage of all CD34 positive vessels within the field. Change in median MVD & PCI following NAC was evaluated using the Wilcoxon’s signed rank test. Results: The median (interquartile range) pre-NAC MVD & PCI values were 76.4/mm2 (46.5 - 106.6/mm2) & 17.3% (6.6 - 30.4%) respectively & post-NAC MVD & PCI values were 72.2/mm2 (50 - 100/mm2) & 25.5% (18.2 - 43.3%) respectively. There was no significant difference between the pre- & post-NAC MVD values (p = 0.48), however, there was a significant difference between the pre- & post-NAC PCI values (p<0.0001) with an increase in PCI following NAC. Conclusions: The MVD of breast tumours following FEC NAC is not significantly different to that measured in the pre-NAC diagnostic core biopsy samples. A significant increase in the PCI of the tumour microvasculature occurs following NAC. This would suggest a differential effect of NAC on the tumour microvasculature according to functional vascular status, with a reduction in the proportion of “immature” blood vessels. No significant financial relationships to disclose.

Phase III Randomized Trial of Doxorubicin and Docetaxel Versus Doxorubicin and Cyclophosphamide As Primary Medical Therapy in Women With Breast Cancer: An Anglo-Celtic Cooperative Oncology Group Study

PURPOSE To compare the clinical and pathologic response rates of doxorubicin and cyclophosphamide (AC) with doxorubicin and docetaxel (AD) as primary chemotherapy in women with primary or locally advanced breast cancer. PATIENTS AND METHODS Eligible patients with histologically proven breast cancer with primary tumors >/= 3 cm, inflammatory or locally advanced disease, and no evidence of metastases were randomly assigned to receive a maximum of six cycles of either doxorubicin (60 mg/m(2)) plus cyclophosphamide (600 mg/m(2)) administered intravenously (IV) every 3 weeks or doxorubicin (60 mg/m(2)) plus docetaxel (75 mg/m(2)) IV every 3 weeks, followed by surgery on completion of chemotherapy. Results A total of 363 patients were randomly assigned to AC (n = 180) or AD (n = 183). A complete clinical response was observed in 17% and 20% of patients treated with AC and AD, respectively (P = .42). Overall (complete and partial) clinical response rates for AC and AD were 61% and 70%, respectively (P = .06). There was no significant difference in either the pathologic complete response rates in the breast with AC (24%) and AD (21%; P = .61) or in the number of patients with positive axillary nodes at surgery with AC (61%) and AD (66%; P = .28). At a median follow-up of 32 months, there is no significant difference between the two groups for the number of relapses. CONCLUSION In contrast to the positive results reported for sequential docetaxel after AC as primary chemotherapy of breast cancer, our data do not suggest a benefit for simultaneous AD over AC.

Dose-dense adjuvant chemotherapy for primary breast cancer.

Adjuvant chemotherapy has been proven to reduce significantly the risk for relapse and death in women with operable breast cancer. Nevertheless, the prognosis for patients presenting with extensive axillary lymph node involvement remains suboptimal. In an attempt to improve on the efficacy of existing chemotherapy, a phase III intergroup trial led by the Cancer and Leukemia Group B (CALGB 97-41) was designed, which tested a mathematical model of tumor growth based on the Norton–Simon hypothesis. This hypothesis, developed about 3 decades ago, and the kinetic model derived from it, created the basis of the concepts of dose density and sequential therapy, both of which were tested in CALGB 97-41. This large prospective randomized trial demonstrated that shortening the time interval between each chemotherapy cycle while maintaining the same dose size resulted in significant improvements in disease-free and overall survival in patients with node-positive breast carcinoma. This finding is highly relevant and has immediate implications for clinical practice.

Adjuvant chemotherapy for primary breast cancer

For patients with hormone-unresponsive or higher-risk operable early-stage breast cancer, adjuvant chemotherapy significantly reduces the risks of relapse and death. The prognosis for such patients, especially those presenting with extensive axillary lymph node involvement, remains poor. New chemotherapy agents and novel administration schedules have recently been shown to improve clinical outcome. This overview provides a summary of the state of the art and the most recent developments regarding adjuvant chemotherapy for primary breast carcinoma.

Dynamic contrast-enhanced MRI and sonography in patients receiving primary chemotherapy for breast cancer

We compared dynamic contrast-enhanced MRI (DCE-MRI) and sonography (US) for monitoring tumour size in 21 patients with breast cancer undergoing primary chemotherapy (PCT) followed by surgery. The correlation between DCE-MRI and US measurements of tumour size, defined as the product of the two major diameters, was 0.555 (P=0.009), 0.782 (P<0.001), and 0.793 (P<0.001) at baseline, and after two and four cycles of PCT, respectively. The median tumour size was significantly larger when measured by DCE-MRI than by US at baseline (1472 vs 900 mm(2), P<0.001) and after two cycles of PCT (600 vs 400 mm(2), P=0.009). After PCT, the median tumour size measured by the two techniques was similar (256 vs 289 mm(2) for DCE-MRI and US, respectively, P=0.859). The correlation with the histopathological major tumour diameter was 0.824 (P<0.001) and 0.705 (P<0.001) for post-treatment DCE-MRI and US, respectively. Measurements of the final major tumour diameter by DCE-MRI tended to be more precise, including cases achieving a pathological complete response. Randomized trials are warranted to establish the clinical impact of the initial discrepancy in tumour size estimates between DCE-MRI and US, and the trend towards a better definition of the final tumour size provided by DCE-MRI in this clinical setting.

Preoperative chemotherapy of continuous infusion of 5-fluorouracil, epirubicin or pirarubicin and cyclophosphamine in operable primary breast cancer

Objective: To evaluate the feasibility and activity of continuous-infusion of fluorouracil in association with epirubicin or pirarubicin and cyclophosphamine as neoadjuvant regimen in patients with primary breast cancer. Methods: A total of 111 (including 114 breasts) were entered into the study. Chemotherapy consisted of two to six cycles of epirubicin 50 mg/(m2·d) and cyclophosphamide 500 mg/(m2·d) on day 1 and 8, and continuous intravenous administration of 5-fluorouracil 200 mg/(m2·d) from day 1 to 28 with a microinfusional elastomer (CEFci) or pirarubicin 35 mg/(m2·d) on day 1 and 8 instead of epirubicin (CTFci). Results: The overall response rate was 87.7%. Forty-five patients (39.5%) attained a complete clinical response and 27 (23.7%) attained a pathological complete response. CTFci regimen was superior to CEFci regimen in response rate, the pathological complete response rate (pCR) of former regimen was significantly higher than that of latter regimen (34.8% vs. 16.2%) (P=0.022). The pCR rate in ER/PgR negative tumor was significantly higher than that of ER/PgR positive tumor, achieving 33.3% and 7.5% respectively (P=0.001, x 2=11.043). There was no relationship between HER-2 expression and tumor response. The toxicity of two regimens was well tolerated. Alopecia was mild in CTFci regimen comparing with CEFci regimen but neutropenia in CTFci regimen was higher than CEFci regimen. Conclusion: Continuous-infusion of fluorouracil in association with epirubicin or pirarubicin and cyclophosphamine is effective regimens as neoadjuvant chemotherapy for primary breast cancer and the toxicity is well tolerated. Pirarubicin regimen was superior to epirubicin regimen in response rate.

A close association between alteration in growth kinetics by neoadjuvant chemotherapy and survival outcome in primary breast cancer

Few surrogate markers are available for predicting the survival benefit from chemotherapy in primary breast cancer. We examined tumor growth kinetics by assessing cytokeratin 18 neo-epitope (CK18NE), an apoptosis marker detected by M30 antibody and Ki-67 antigen, a proliferation marker detected by MIB-1 antibody in 72 primary breast cancer patients who underwent pre-operative anthracycline-based chemotherapy. Increase in M30 index and decrease in MIB-1 index after the exposure of 2 to 4 cycles of chemotherapy correlated significantly with pathological tumor response. Univariate survival analysis, conducted in the subgroup of 42 patients who underwent CAF (cyclophosphamide, adriamycin and 5-FU) therapy alone, showed that the patients with the high levels of M30 index (>35 counts/1000 tumor cells) and the low levels of MIB-1 index (<140 counts/1000 tumor cells) after chemotherapy had a remarkably favorable prognosis as compared with patients in other categories. In addition, the alteration in growth kinetics by the treatment showed a significant prognostic value. Multivariate analysis also confirmed that the post-treatment growth kinetics was an independent prognostic indicator. These findings suggest that the alteration in growth kinetics revealed by CK18NE and MIB-1 might be a surrogate marker for predicting the survival benefit from chemotherapy in primary breast cancer.