Prediction of outcome in locally advanced breast cancer by post-chemotherapy nodal status and baseline serum tumour markers

In spite of the apparent improvement in outcome in locally advanced breast cancer, the prognosis remains dismal in many patients. The aim of this study was to define prognostic subgroups within this heterogeneous entity. Between 1990 and 1999, 104 consecutive patients with locally advanced breast cancer were treated by a multimodality programme consisting of 4-6 courses of CAF induction chemotherapy followed by surgery, breast-conserving when feasible. In most cases, chemotherapy was then resumed, up to a total of eight courses, followed by locoregional radiation therapy. Patients with hormone receptor-positive tumours received tamoxifen (20 mg day(-1)) for 5 years. At a median follow-up of 57 months, the 5-year overall survival for the entire group and the disease-free survival for the 94 operated patients were 65% and 53%, respectively. Univariate analysis identified 10 prognostic factors of overall and disease-free survival, of which four retained significance on multivariate analysis: inflammatory breast cancer (P=0.0000, P=0.0004, respectively), baseline tumour markers (P=0.003 for both), post-chemotherapy number of involved nodes (P=0.003; P=0.017) and extracapsular spread (P=0.052; P=0.014). In conclusion, besides inflammatory features, baseline tumour markers and post-chemotherapy nodal status are strong predictors of outcome in locally advanced breast cancer.     

The Efficacy of Neoadjuvant Chemotherapy Compared to Postoperative Therapy in the Treatment of Locally Advanced Breast Cancer

The current approach to the treatment of locally advanced breast cancer is sequential chemotherapy, surgery and/or radiation, and consolidation chemotherapy. Although significant tumor response is seen with this regimen, there are few studies that compare this approach to postoperative chemotherapy. The purpose of this study was to compare the disease-free and overall survival of patients with locally advanced breast cancer treated with neoadjuvant chemotherapy and surgery to patients treated with surgery followed by adjuvant chemotherapy. Ninety-four patients with stage IIB, MA, and MB breast cancer were treated with a standardized chemotherapy regimen. The first group, 60 patients who were followed prospectively, was treated with neoadjuvant chemotherapy (NCT) consisting of vincristine, prednisone, Cytoxan, methotrexate, and 5-FU (CVFMP) followed by surgery and consolidation chemotherapy with adriamycin. The second group, 34 patients evaluated retrospectively, had surgery followed by postoperative chemotherapy (PCT) with CVFMP followed by adriamycin. Overall median follow-up was 38 months. In the NCT group, 45/60 (75%) patients had a clinical response to induction therapy and the median reduction in tumor size was 50%. The rates of local recurrence, distant recurrence, and death from disease were similar in the two groups. The time to local recurrence was similar for the two groups. However, the median time to distant recurrence was shorter in the NCT group (19 month vs. 31 months, p = NS). Overall median survival among the NCT patients was shorter than for the PCT group (30 vs. 47 months, p = NS). The current study suggests that postoperative therapy is comparable to a neoadjuvant regimen in patients with locally advanced breast cancer with regard to local recurrence, distant recurrence, and overall survival.     

High expression of ATP-binding cassette transporter ABCC11 in breast tumors is associated with aggressive subtypes and low disease-free survival

ATP-binding cassette (ABC) transporters are membrane proteins that efflux various compounds from cells, including chemotherapeutic agents, and are known to affect multidrug resistance. Recent reports disagree on whether ABCC11 is a risk factor for breast tumorigenesis, but its expression in breast cancer is poorly investigated. We hypothesized that both frequency and expression levels of ABC transporters in breast tumors would vary by cancer subtype, and be associated with prognosis. Here, we constructed a tissue microarray breast tumor samples from 281 patients, and analyzed expressions of ABCB1, ABCC1, ABCC11, and ABCG2 immunohistochemically. Breast cancer subtypes were determined by immunohistochemistry of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2). Protein expression was correlated to clinicopathological characteristics, clinical follow-up, and pathological complete response to neoadjuvant chemotherapy. The tissue microarray comprised 191 luminal A (68.0 %), 17 luminal B (6.0 %), 27 HER2 (9.6 %), and 46 triple-negative (16.4 %) samples. ABCC1 and ABCC11 expressions were associated with significantly shorter disease-free survival (P = 0.027 and P = 0.003, respectively). ABCC1, ABCC11, and ABCG2, but not ABCB1, were expressed significantly more, and more frequently, in aggressive subtypes. Patients with HER2+ and triple-negative tumor subtypes that expressed high levels of ABCC11 had significantly worse disease-free survival (P = 0.017 and P < 0.001, respectively). We have shown, for the first time, that ABCC1, ABCC11, and ABCG2 are highly expressed in aggressive breast cancer subtypes, and that tumor ABCC11 expression is associated with poor prognosis.     

Platinum-Based Induction Chemotherapy Followed by Radiation as Definitive Treatment for Patients with Locally Advanced Cancer of the Oral Cavity,Oropharynx and Hypopharynx. A Retrospective Analysis of 32 Cases

Summary

Thirty-two patients with locally advanced cancer of oral cavity, oropharynx and hypopharynx were treated with three cycles of platinum-based induction chemotherapy followed by radiation therapy. After completion of the combined treatment 50% of the patients were in complete response (CR) and 28% in partial response (PR). So far, 24 patients have died. Local progression occurred in 20 patients. Survival is 29% at 24 months. Seven (22%) patients remain alive and have been disease-free for 22-59 months.

In conclusion, induction chemotherapy followed by radiation therapy may omit radical surgery, without compromising survival, in some patients with locally advanced cancer of the oral cavity, oropharynx and hypopharynx.     

Effects of Genetic Polymorphisms in the ABCB1 Gene onClinical Outcomes in Patients with Gastric Cancer Treated bySecond-line Chemotherapy

Objective: Tumor cells that overexpress P-glycoprotein (Pgp) may be resistant to several anticancer agentsdue to altered pharmacokinetics and reduced intracellular concentrations of the anticancer agents. Pgp is encodedby the ATP binding cassette gene B1 (ABCB1). To our knowledge, only one previous report has evaluated theeffect of ABCB1 gene polymorphisms on clinical outcomes of gastric cancer. The purpose of this analysis was toevaluate the impact of genetic polymorphisms of the ABCB1 gene on clinical outcomes in patients with advancedgastric cancer (AGC) treated with second-line chemotherapy. Methods: We retrospectively analyzed the impactof ABCB1 gene polymorphisms (ABCB1 3435C>T) on clinical outcomes in 100 patients with AGC who receivedsecond-line chemotherapy. Results: Median overall survival (OS) since the initiation of second-line chemotherapywas 6.0 months (95% confidence interval [CI], 4.8 to 8.0 months), and median progression-free survival (PFS)was 2.7 months (95% CI, 2.1 to 3.4 months). In a multivariate analysis of PFS, a 3435 CC polymorphism (n =45) was significantly associated with longer PFS compared with the CT/TT type polymorphism (n = 55), withborderline significance (PFS of 3.2 months vs. 2.2 months, respectively; HR 1.50; 95% CI, 0.98-2.30; P = 0.061).ABCB1 3435 C>T polymorphisms were not associated with OS. No interaction was seen between ABCB1polymorphisms and treatment regimens. Conclusion: Genetic polymorphisms of ABCB1 3435C>T might havea possible impact on clinical outcomes of second-line chemotherapy in AGC. Further prospective evaluationusing a larger sample size is required.     

Locally advanced non inflammatory breast cancer treated by combined chemotherapy and preoperative irradiation: updated results in a series of 120 patients]

PURPOSE: To evaluate our updated data concerning survival and locoregional control in a study of locally advanced non inflammatory breast cancer after primary chemotherapy followed by external preoperative irradiation. PATIENTS AND METHODS: Between 1982 and 1998, 120 patients (75 stage IIIA, 41 stage IIIB, and 4 stage IIIC according to AJCC staging system 2002) were consecutively treated by four courses of induction chemotherapy with anthracycline-containing combinations followed by preoperative irradiation (45 Gy to the breast and nodal areas) and a fifth course of chemotherapy. Three different locoregional approaches were proposed, depending on tumour characteristics and tumour response. After completion of local therapy, all patients received a sixth course of chemotherapy and a maintenance adjuvant chemotherapy regimen without anthracycline. The median follow-up from the beginning of treatment was 140 months. RESULTS: Mastectomy and axillary dissection were performed in 49 patients (with residual tumour larger than 3 cm in diameter or located behind the nipple or with bifocal tumour), and conservative treatment in 71 patients (39 achieved clinical complete response or partial response >90% and received additional radiation boost to initial tumour bed; 32 had residual mass or=6 cm in diameter, p =0.002). Ten-year overall metastatic disease-free survival rate was 61%. After multivariate analysis, metastatic disease-free survival rates were significantly influenced by clinical stage (stage IIIA-B vs. IIIC, p =0.0003), N-stage (N0 vs. N1-2a, and 3c, p =0.017), initial tumour size (<6 vs. >or=6 cm in diameter, p =0.008), and tumour response after induction chemotherapy and preoperative irradiation (clinically complete response + partial response vs. non-response, p =0.0015). In the non conservative breast treatment group, of the 32 patients with no change in clinical tumour size after induction chemotherapy, the 10-year metastatic disease-free survival rate was 59% with only one local relapse. Arm lymphedema was noted in 17% (14 of 81) following axillary dissection and in 2.5% (1 of 39) without axillary dissection. Cosmetic results were satisfactory in 70% of patients treated by irradiation alone and in 51.5% of patients after wide excision and irradiation. CONCLUSION: Despite the poor prognosis of patients with locally advanced non inflammatory breast cancer resistant to primary anthracycline-based regimen, aggressive locoregional management using preoperative irradiation and mastectomy with axillary dissection offers a possibility of long term survival with low local failure rate for patients without extensive nodal disease. On the other hand, the rate of local failure seems to be high in patients with clinical partial tumour response following induction chemotherapy and breast-conserving treatment combining preoperative irradiation and large wide excision.     

The role of surgery in the combined treatment of locally advanced breast cancer

Sixty patients with stage IIIA and IIIB breast cancer have been treated with a combined modality approach including induction chemotherapy, surgery and adjuvant chemotherapy: 74.5% of patients achieved an objective response after 3 cycles of induction chemotherapy, and 98.3% of patients were rendered disease-free after induction chemotherapy and surgery or radiotherapy; at 4 years, actuarial survival and disease-free survival are 71.5% and 43%, respectively. These results are significantly better than our historical control, and locally advanced breast cancer must now be considered a curable disease when treated with an aggressive multimodal approach.     

Impact of clinical, pathologic, and treatment-related factors on outcome in patients with locally advanced breast cancer treated with multimodality therapy

The authors reviewed the experience at their institution treating patients with locally advanced breast cancer using multimodality therapy to identify clinical, pathologic, and treatment-related factors affecting outcome. One hundred patients with locally advanced breast cancer were treated with definitive therapy at William Beaumont Hospital. Three patients had stage IIB disease, 45 patients had stage IIIA disease, and 52 patients had IIIB disease. Thirteen patients had inflammatory breast carcinoma. Seventy-four patients (74%) received trimodality therapy consisting of systemic therapy, radiation therapy, and surgery. Systemic therapy was delivered to 90 patients. Eighty-three patients (83%) received adjuvant radiation therapy. Eighty-five patients underwent mastectomy (85%). Multiple clinical, pathologic, and treatment-related factors were analyzed for their impact on outcome. The median follow-up was 47 months. Overall, the 5-year actuarial rates of local control, disease-free survival, overall survival, and cause-specific survival were 81%, 43%, 53%, and 55%, respectively. The 5-year actuarial cause-specific survival rates for patients with inflammatory breast carcinoma, stage IIIA disease, and stage IIIB disease were 25%, 55%, and 53%, respectively. On multivariate analysis, local control was improved with radiation therapy (p = 0.008) and the absence of inflammatory breast carcinoma (p = 0.008). Disease-free survival was improved with the addition of radiation therapy (p = 0.001) and with less than four positive lymph nodes (p = 0.003). Distant metastasis-free survival was improved in patients without inflammatory breast carcinoma (p = 0.0249) and with less than four involved lymph nodes (p = 0.0135). Cause-specific survival and overall survival were adversely affected by the presence of inflammatory breast carcinoma (p = 0.0135 and p = 0.0325, respectively) or four or more involved lymph nodes (p = 0.0082 and p = 0.012, respectively). Radiation therapy appears to be a critical component in the overall treatment of patients with locally advanced breast cancer by improving the rates of local control and disease-free survival. Other adverse factors for survival include four or more positive lymph nodes and inflammatory breast carcinoma.     

Predictive potential of ABCB1, ABCC3, and GSTP1 gene polymorphisms on osteosarcoma survival after chemotherapy

Genetic polymorphisms in drug metabolism and transport genes can influence the pharmacokinetics and pharmacodynamics of chemotherapy drugs. We investigated the role of genes involved in metabolic and transport pathways in response to chemotherapy and clinical outcome of osteosarcoma patients. The association between the eight polymorphisms with response to chemotherapy and clinical outcome of patients was carried out by unconditional logistic regression analysis and Cox proportional hazard models. Of 186 patients, 98 patients showed good response to chemotherapy, 64 died, and 97 showed progression at the end of the study. Patients carrying ABCB1 rs1128503 TT genotype and T allele were more likely to have a good response to chemotherapy. ABCC3 rs4148416 TT genotype and T allele and GSTP1 rs1695 GG genotype and G allele were associated with poor response to chemotherapy. In the Cox proportional hazards model, after adjusting for potential confounding factors, patients carrying ABCB1 rs1128503 TT genotype and T allele were associated with lower risk of progression-free survival (PFS) and overall survival (OS). ABCC3 rs4148416 TT genotype and T allele and GSTP1 rs1695 GG genotype and G allele were correlated with high risk of PFS and OS. The ABCB1 TT and GSTP1 GG genotypes were significantly associated with a shorter OS. In conclusion, variants of ABCB1 rs128503, ABCC3 rs4148416, and GSTP1 rs1695 are associated with response to chemotherapy and PFS and OS of osteosarcoma patients; these gene polymorphisms could help in the design of individualized therapy.     

Phase II trial of preoperative S-1 plus cisplatin followed by surgery for initially unresectable locally advanced gastric cancer

Background

The aim of this study was to evaluate the efficacy and feasibility of preoperative chemotherapy with S-1 plus cisplatin in patients with initially unresectable locally advanced gastric cancer.

Methods

We enrolled patients with initially unresectable locally advanced gastric cancer because of severe lymph node metastases or invasion of adjacent structures. Preoperative chemotherapy consisted of S-1 at 80 mg/m² divided in two daily doses for 21 days and cisplatin at 60 mg/m² intravenously on day 8, repeated every 35 days. If a tumor decreased in size, patients received 1 or 2 more courses. Surgery involved radical resection with D2 lymphadenectomy.

Results

Between December 2000 and December 2007, 27 patients were enrolled on the study. No CR was obtained, but PR was seen in 17 cases, and the response rate was 63.0%. Thirteen patients (48.1%) had R0 resections. There were no treatment related deaths. The median overall survival time (MST) and the 3-year overall survival (OS) of all patients were 31.4 months and 31.0%, respectively. Among the 13 patients who underwent curative resection, the median disease-free survival (DFS) and the 3-year DFS were 17.4 months and 23.1%, respectively. The MST and the 3-year OS were 50.1 months and 53.8%, respectively. The most common site of initial recurrence after the R0 resection was the para-aortic lymph nodes.

Conclusions

Preoperative S-1 plus cisplatin can be safely delivered to patients undergoing radical gastrectomy. This regimen is promising as neoadjuvant chemotherapy for resectable gastric cancer. For initially unresectable locally advanced gastric cancer, new trials using more effective regimens along with extended lymph node dissection are necessary.     

Loss of Tumor Suppressor ARID1A Protein Expression Correlates with Poor Prognosis in Patients with Primary Breast Cancer

Purpose

Somatic mutations of the chromatin remodeling AT-rich interactive domain 1A (SWI-like) gene (ARID1A) have been identified in many human cancers, including breast cancer. The purpose of this study was to evaluate the nuclear expression of ARID1A in breast cancers by immunohistochemistry (IHC) and to correlate the findings to clinicopathologic variables including prognostic significance.

Methods

IHC was performed on tissue microarrays of 476 cases of breast cancer. Associations between ARID1A expression and clinicopathologic characteristics and molecular subtype were retrospectively analyzed.

Results

Low expression of ARID1A was found in 339 of 476 (71.2%) cases. Low expression of ARID1A significantly correlated with positive lymph node metastasis (p=0.027), advanced pathologic stage (p=0.001), low Ki-67 labeling index (p=0.003), and negative p53 expression (p=0.017). The ARID1A low expression group had significantly shorter disease-free and overall survival than the ARID1A high expression group (p<0.001 and p<0.001, respectively). Multivariate analysis demonstrated that low expression of ARID1A was a significant independent predictive factor for poor disease-free and overall survival in patients with breast cancer (disease-free survival: hazard ratio, 0.38, 95% confidence interval [CI], 0.20-0.73, p=0.004; overall survival: hazard ratio, 0.11, 95% CI, 0.03-0.46, p=0.003). In patients with luminal A type disease, patients with low ARID1A expression had significantly shorter disease-free and overall survival rates than patients with high ARID1A expression (p=0.022 and p=0.018, respectively).

Conclusion

Low expression of ARID1A is an independent prognostic factor for disease-free and overall survival in breast cancer patients and may be associated with luminal A type disease. Although the biologic function of ARID1A in breast cancer remains unknown, low expression of ARID1A can provide valuable prognostic information.     

Expression of PD-L1 in Locally Advanced Breast Cancer and Its Impact on Neoadjuvant Chemotherapy Response

Objectives: Programmed cell death-ligand 1 (PD-L1) is a new target in breast cancer (BC) and its impact on neoadjuvant chemotherapy (NACTH) response is still unclear. The aim of this study was to investigate the prevalence of PD-L1 in locally advanced invasive BC of different molecular subtypes and to elucidate its relation to tumor-infiltrating lymphocytes (TILs) density, established clinicopathological factors, pathological therapy response after neoadjuvant chemotherapy and patients’ outcome. Materials and Methods: One hundred and five cases of locally advanced invasive BC were enrolled in our study. Cases were classified into five molecular subtypes according to the Immuno-histochemical data. PD-L1 immunostaining was analyzed for all studied cases and its expression was correlated with TILs density, histopathologic parameters, BC molecular subtypes, Pathological therapy response, 7-years disease-free survival (DFS) and overall survival (OS). Results: PD-L1 was expressed in 32.4% of the studied locally advanced BC cases. It showed a significant correlation with old age group (p= 0.010), high tumor grade (p= 0.046) and high pretherapy TILs density (p= <0.001). PD-L1 expression was higher in HER2/neu-enriched group (45.5%) followed by TNBC (44.4%). There were no significant relations between PD-L1 expression and DFS, OS as well as pathological therapy response, although, it revealed more expression in cases with complete and marked therapy response. Conclusion: In spite our results fail to prove that PD-L1 is a bad prognostic biomarker in locally advanced BC, but they indicate PD-L1 could be a new target for the treatment of patients with high grade breast carcinoma and TNBC group.     

Over-expression of Skp2 is associated with resistance to preoperative doxorubicin-based chemotherapy in primary breast cancer

Introduction

Preoperative chemotherapy is often used in patients with locally advanced breast cancer. However, commonly used clinical and pathological parameters are poor predictors of response to this type of therapy. Recent studies have suggested that altered regulation of the cell cycle in cancer may be involved in resistance to chemotherapy. Over-expression of the ubiquitin ligase Skp2 results in loss of the cell cycle inhibitor p27^Kip1 and is associated with poor prognosis in early breast cancer. The purpose of the present study was to examine the role of these proteins as predictors of clinical outcome and response to chemotherapy in locally advanced breast cancer.

Methods

The expression levels of Skp2 and p27^Kip1 were determined by immunohistochemistry both before and after preoperative chemotherapy in 40 patients with locally advanced breast cancer. All patients were treated with cyclophosphamide/doxorubicin (adriamycin)/5-fluorouracil (CAF) and some patients received additional treatment with docetaxel. Expression data were compared with patients' clinical and pathological features, clinical outcome, and response to chemotherapy.

Results

Skp2 expression before preoperative chemotherapy was inversely related to p27^Kip1 levels, tumor grade, and expression of estrogen and progesterone receptors. Both Skp2 and p27^Kip1 were found to be accurate prognostic markers for disease-free and overall survival. High preoperative expression of Skp2 was associated with resistance to CAF therapy in 94% of patients (P < 0.0001) but not with resistance to docetaxel.

Conclusion

Skp2 expression may be a useful marker for predicting response to doxorubicin-based preoperative chemotherapy and clinical outcome in patients with locally advanced breast cancer.     

A comprehensive study of polymorphisms in ABCB1, ABCC2 and ABCG2 and lung cancer chemotherapy response and prognosis

ATP-binding cassette (ABC) transporter expression and genetic heterogeneity have been implicated in response to anticancer therapy. This study characterized genetic variability of the ABCB1 (also known as MDR1), ABCC2 (MRP2) and ABCG2 (BCRP) genes, which are key players in the metabolism of many chemotherapeutic agents including those used in the treatment of lung cancer. We genotyped 53 polymorphisms in the candidate genes in genomic DNA samples of 171 cases of small cell lung carcinoma (SCLC) and 206 cases of non-small cell lung carcinoma (NSCLC), and studied their impact on early response to chemotherapy, progression-free survival and overall survival. SNP rs717620 in ABCC2 was moderately associated with a poor response to chemotherapy but strongly with shorter progression-free survival and overall survival in SCLC but not NSCLC patients, indicating that ABCC2 genetic variation is an important factor in SCLC survival after chemotherapy.     

Associations of ABCB1, ABCC2, and ABCG2 polymorphisms with irinotecan-pharmacokinetics and clinical outcome in patients with advanced non-small cell lung cancer

BACKGROUND: The authors investigated whether ABCB1, ABCC2, and ABCG2 genetic polymorphisms affect pharmacokinetics (PK) of irinotecan and treatment outcome of patients with advanced nonsmall cell lung cancer (NSCLC). METHODS: Blood samples from 107 NSCLC patients treated with irinotecan and cisplatin chemotherapy were used for genotyping ABCB1 (1236C > T, 2677G > T/A, 3435C > T), ABCC2 (-24C > T, 1249G > A, 3972C > T), and ABCG2 (34G > A, 421C > A) polymorphisms. Genotypes were correlated with irinotecan-PK, toxicity, tumor response, and survival. RESULTS: Among 8 polymorphisms, 3435TT and 2677TT were associated with AUC(SN-38G) and CL(SN-38G). When haplotypes are assigned, 2677TT/3435TT carriers showed significantly lower AUC(SN-38G) (P = .006), whereas 2677GG/3435CC carriers showed significantly higher AUC(SN-38) (P = .039). These findings suggest that 2677TT and 3435TT variants are associated with higher efflux activity. In toxicity, the 2677G/T or A was associated with grade 4 neutropenia. The 2677GG carriers showed significantly lower absolute neutrophil count during the 1(st) cycle (P = .012) as well as entire course of chemotherapy (P = .042). The 3435TT was associated with higher frequency of grade 3 diarrhea (P = .047). In tumor response, ABCC2 -24TT and 3972TT genotypes were associated with higher response rates (P = .031 and .046, respectively) and longer progression-free survival (P = .035 and .038, respectively), which was sustained in haplotype analysis. CONCLUSIONS: Specific polymorphisms of ABCB1 and ABCC2 can influence disposition and tumor response to irinotecan by regulating transporter activity. These findings may help to individualize irinotecan-based chemotherapy in patients with advanced NSCLC.     

Expression of multidrug resistance-associated protein1,P-glycoprotein,and thymidylate synthase in gastric cancer patients treated with 5-fluorouracil and doxorubicin-based adjuvant chemotherapy after curative resection

Both 5-fluorouracil and doxorubicin are commonly used agents in chemotherapy of gastric cancer in adjuvant setting as well as metastatic disease. In a variety of malignancies, high expression of multidrug resistance-associated protein1 and P-glycoprotein has been associated with resistance to doxorubicin, whereas 5-fluorouracil resistance has correlated with the level of thymidylate synthase expression. We evaluated the expression of multidrug resistance-associated protein1, P-glycoprotein, and thymidylate synthase using immunohistochemistry in 103 locally advanced gastric cancer patients (stage IB-IV) who underwent 5-fluorouracil and doxorubicin-based adjuvant chemotherapy after curative resection and investigated the association between their expression and clinicopathologic characteristics including prognosis of the patients. While high expression (> or =5% of tumour cells positive) of multidrug resistance-associated protein1 and P-glycoprotein was observed in 70 patients (68%) and 42 patients (41%), respectively, 65 patients (63%) had primary tumours with high expression (> or =25% of tumour cells positive) of thymidylate synthase. There was a significant association between multidrug resistance-associated protein1 and P-glycoprotein expression (P<0.0001) as well as P-glycoprotein and thymidylate synthase expression (P<0.0001). High multidrug resistance-associated protein1 and P-glycoprotein expressions were associated with well and moderately differentiated histology (P<0.0001 and P=0.03, respectively) and intestinal type (P<0.0001 and P=0.009, respectively). High multidrug resistance-associated protein1 expression correlated with lymph node metastasis (P=0.037), advanced stage (P=0.015), and older age (P=0.021). Five-year disease-free survival and overall survival of total patients were 55.2% and 56.2%, respectively, with a median follow-up of 68 months. There were no significant differences in disease-free survival and overall survival according to the expression of multidrug resistance-associated protein1 (P=0.902 and P=0.975, respectively), P-glycoprotein (P=0.987 and P=0.955, respectively), and thymidylate synthase (P=0.604 and P=0.802, respectively). Concurrent high expression of these proteins (high multidrug resistance-associated protein1/P-glycoprotein, high multidrug resistance-associated protein1/thymidylate synthase, high P-glycoprotein/thymidylate synthase) did not correlate with disease-free survival or overall survival. Even high expression of all three proteins was not associated with poor disease-free survival (P=0.919) and overall survival (P=0.852). In conclusion, high expression of multidrug resistance-associated protein1, P-glycoprotein, and thymidylate synthase did not predict poor prognosis of gastric cancer patients treated with 5-fluorouracil and doxorubicin-based adjuvant chemotherapy. A larger study including patients treated with surgical resection alone would be necessary.     

Reduced MLH1 expression in breast tumors after primary chemotherapy predicts disease-free survival.

PURPOSE: Loss of function or expression of the mismatch repair protein MLH1 and the tumor suppressor protein p53 have been implicated in acquired resistance to anticancer drugs. We have compared the expression of MLH1 and p53 in tumors from women with clinically node-positive breast cancer before and after primary (neoadjuvant) chemotherapy. Further, we have assessed the value of these markers as predictors of response to therapy by correlation with disease-free survival. PATIENTS AND METHODS: Immunohistochemistry scores of MLH1 and p53 expression were made on 36 tru-cut prechemotherapy biopsies and 29 paired postchemotherapy tumor samples. The significance of the change in scores and their correlation with disease-free survival were evaluated by the Wilcoxon signed rank sum test and Cox proportional hazards regression analysis, respectively. RESULTS: Primary chemotherapy results in a significant reduction in the percent of cells expressing MLH1 (P =.010). This change in MLH1 expression after chemotherapy is strongly associated with poor disease-free survival (P =.0025). Expression of p53 was not significantly altered by chemotherapy. Neither MLH1 nor p53 expression before chemotherapy predicted disease-free survival or tumor response to chemotherapy. Low MLH1 expression after chemotherapy was an independent predictor of poor disease-free survival on multivariate Cox analysis when considered with other clinicopathologic prognostic factors. CONCLUSION: Tumor cells that have reduced MLH1 expression seem to have a survival advantage during combined chemotherapy of locally advanced breast cancers, which supports the hypothesis that loss of MLH1 has a role in drug resistance. MLH1 expression after chemotherapy is an independent predictive factor for poor disease-free survival and may, therefore, define a group of patients with drug-resistant breast cancer.     

Docetaxel

? Docetaxel is an antimicrotubule agent established as a first- and/or second-line intravenous therapy in a variety of cancers, including locally advanced or metastatic breast cancer. It also is approved in the US as adjuvant therapy in early breast cancer, and continues to be investigated in this setting in combination with other agents and in various dosing schedules. ? The efficacy of docetaxel-containing adjuvant therapy has been evaluated in two large (n >1000 per trial), randomized clinical trials. One trial compared intravenous docetaxel plus doxorubicin and cyclophosphamide (TAC) every 3 weeks with standard fluorouracil plus doxorubicin and cyclophosphamide (FAC) chemotherapy. Another trial compared intravenous docetaxel plus cyclophosphamide (TC) every 3 weeks with doxorubicin plus cyclophosphamide (AC). ? Treatment with TAC improved disease-free survival (75% vs 68%; p = 0.001) and overall survival (87% vs 81%; p = 0.008) at 55 months to a greater extent than FAC. ? There were no significant differences in disease-free survival and overall survival between TC and AC. Nevertheless, a nonsignificant trend in disease-free survival favors TC and follow-up data were for a period of only 43 months. ? Tolerability in docetaxel-containing adjuvant chemotherapy regimens was manageable. The most frequently reported severe adverse events with TAC were predominantly hematologic, including neutropenia, febrile neutropenia, and neutropenic infection.