Efficacy of adjuvant aromatase inhibitor in hormone receptor-positive postmenopausal breast cancer patients according to the body mass index

Background:

Increased adiposity may trigger signalling pathways that induce aromatase expression. As aromatase inhibitors exert their effects by blocking the aromatase enzyme, higher body mass index (BMI) can reduce the effect of aromatase inhibitors. Thus, we aimed to investigate retrospectively the effect of BMI on the efficacy of aromatase inhibitors in hormone receptor-positive postmenopausal patients with breast cancer.

Methods:

Newly diagnosed hormone receptor-positive breast cancer patients who were postmenopausal and non-metastatic were enrolled to the study. Patients with BMI ranging between 18.5 and 24.9 kg m⁻² were considered as normal weight patients (Arm A, n=102), and patients with a BMI ranging ⩾25 kg m⁻² were grouped as overweight and obese patients (Arm B, n=399).

Results:

In both normal weight and overweight patients, the baseline clinico-pathologic properties and the treatment history with radiotherapy and chemotherapy were similar, and with no statistically significant difference. In normal weight patients disease-free survival (DFS) rate was 93.7% and 77.6%, whereas in overweight and obese patients DFS rate was 96.8% and 85.5% in the first and third years, respectively, (P=0.08). Three year survival rate in Arm A patients was 98.3%, whereas in Arm B was 98.0% (P=0.57). When anastrozole was compared with letrozole in the subgroup analysis no difference with regard to DFS and overall survival was detected.

Conclusion:

These results, contradictory to the prior results, show that BMI has no worse effect on outcomes of aromatase inhibitors in postmenopausal hormone receptor-positive breast cancer patients. In the subgroup analysis, letrozole and anastrozole had similar survival outcomes.     

Change in the hormone receptor status following administration of neoadjuvant chemotherapy and its impact on the long-term outcome in patients with primary breast cancer

Background:

To evaluate the impact of change in the hormone receptor (HR) status (HR status conversion) on the long-term outcomes of breast cancer patients treated with neoadjuvant chemotherapy (NAC).

Methods:

We investigated 368 patients for the HR status of their lesions before and after NAC. On the basis of the HR status and the use/non-use of endocrine therapy (ET), the patients were categorised into four groups: Group A, 184 ET-administered patients with HR-positive both before and after NAC; Group B, 47 ET-administered patients with HR status conversion; Group C, 12 ET-naive patients with HR status conversion; Group D, 125 patients with HR-negative both before and after NAC.

Results:

Disease-free survival in Group B was similar to that in Group A (hazard ratio, 1.16; P=0.652), but that in Group C was significantly lesser than that in Group A (hazard ratio, 6.88; P<0.001). A similar pattern of results was obtained for overall survival.

Conclusion:

Our results indicate that the HR status of tumours is a predictive factor for disease-free and overall survival and that ET appears to be suitable for patients with HR status conversion. Therefore, both the CNB and surgical specimens should be monitored for HR status.     

Everolimus in metastatic renal cell carcinoma patients intolerant to previous VEGFr-TKI therapy: a RECORD-1 subgroup analysis

Background:

A relevant percentage of patients with metastatic renal cell carcinoma develop intolerance to vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFr-TKIs) and require careful selection of subsequent treatment. This retrospective analysis evaluated the safety and efficacy of everolimus in patients enrolled in the phase-III RECORD-1 trial who discontinued previous VEGFr-TKI therapy because of toxicity.

Methods:

Patients with an adverse event (AE) as their primary reason for discontinuation of previous VEGFr-TKI therapy were included. Median progression-free survival (PFS) for VEGFr-TKI-intolerant patients in each arm was estimated using the Kaplan–Meier method, and effect on PFS (hazard ratio (HR)) was calculated using the Cox proportional hazard model.

Results:

In VEGFr-TKI-intolerant patients (n=58, 14%), median PFS was 5.4 months with everolimus and 1.9 months with placebo (HR: 0.32; P=0.004). In sunitinib-intolerant patients (n=26), median PFS was 5.1 months with everolimus and 2.8 months with placebo (HR: 0.28; P=0.033). Grade 3/4 AEs reported with everolimus in VEGFr-TKI-intolerant patients included infections (16%), fatigue (7%) and stomatitis (4%). The toxicity profile of everolimus was similar in the VEGFr-TKI-intolerant and overall study populations.

Conclusion:

Everolimus is well tolerated and efficacious with no increased toxicity in patients intolerant to VEGFr-TKI therapy.     

Sex and the clinical value of body mass index in patients with clear cell renal cell carcinoma

Background:

An increased body mass index (BMI) is significantly associated with favourable prognosis in renal cell carcinoma (RCC). This study investigated the associations among sex, BMI, and prognosis in clear cell RCC patients.

Methods:

We retrospectively analysed 435 patients with clear cell RCC who underwent a nephrectomy. The associations among sex, BMI, clinicopathologic factors, and cancer-specific survival (CSS) were analysed.

Results:

As a continuous variable, increased BMI was associated with higher CSS rate by univariate analysis in the whole population (hazard ratio, 0.888 per kg m^–2; 95% confidence interval, 0.803–0.982; P=0.021). A sub-population analysis by sex demonstrated that BMI was significantly associated with CSS in men (P=0.004) but not in women (P=0.725). Multivariate analysis revealed BMI to be an independent predictor of CSS in only men.

Conclusion:

Body mass index was significantly associated with clear cell RCC prognosis. However, the clinical value of BMI may be different between men and women.     

The role of Cathepsin S as a marker of prognosis and predictor of chemotherapy benefit in adjuvant CRC: a pilot study

Background:

The aim of this pilot retrospective study was to investigate the immunohistochemical expression of Cathepsin S (CatS) in three cohorts of colorectal cancer (CRC) patients (n=560).

Methods:

Prevalence and association with histopathological variables were assessed across all cohorts. Association with clinical outcomes was investigated in the Northern Ireland Adjuvant Chemotherapy Trial cohort (n=211), where stage II/III CRC patients were randomised between surgery-alone or surgery with adjuvant fluorouracil/folinic acid (FU/FA) treatment.

Results:

Greater than 95% of tumours had detectable CatS expression with significantly increased staining in tumours compared with matched normal colon (P>0.001). Increasing CatS was associated with reduced recurrence-free survival (RFS; P=0.03) among patients treated with surgery alone. Adjuvant FU/FA significantly improved RFS (hazard ratio (HR), 0.33; 95% CI, 0.12–0.89) and overall survival (OS; HR, 0.25; 95% CI, 0.08–0.81) among 36 patients with high CatS. Treatment did not benefit the 66 patients with low CatS, with a RFS HR of 1.34 (95% CI, 0.60–3.19) and OS HR of 1.33 (95% CI, 0.56–3.15). Interaction between CatS and treatment status was significant for RFS (P=0.02) and OS (P=0.04) in a multivariate model adjusted for known prognostic markers.

Conclusion:

These results signify that CatS may be an important prognostic biomarker and predictive of response to adjuvant FU/FA in CRC.     

Androgen receptor expression predicts beneficial tamoxifen response in oestrogen receptor-α-negative breast cancer

Background:

Although the androgen receptor (AR) is frequently expressed in breast cancer, its relevance in the disease is not fully understood. In addition, the relevance of AR in determining tamoxifen treatment efficiency requires evaluation.

Purpose:

To investigate the tamoxifen predictive relevance of the AR protein expression in breast cancer.

Methods

Patients were randomised to tamoxifen 40 mg daily for 2 or 5 years or to no endocrine treatment. Mean follow-up was 15 years. Hazard ratios were calculated with recurrence-free survival as end point.

Results:

In patients with oestrogen receptor (ER)-negative tumours, expression of AR predicted decreased recurrence rate with tamoxifen (hazard ratio (HR)=0.34; 95% confidence interval (CI)=0.14–0.81; P=0.015), whereas the opposite was seen in the AR− group (HR=2.92; 95% CI=1.16–7.31; P=0.022). Interaction test was significant P<0.001. Patients with triple-negative and AR+ tumours benefitted from tamoxifen treatment (HR=0.12; 95% CI=0.014–0.95 P=0.044), whereas patients with AR− tumours had worse outcome when treated with tamoxifen (HR=3.98; 95% CI=1.32–12.03; P=0.014). Interaction test was significant P=0.003. Patients with ER+ tumours showed benefit from tamoxifen treatment regardless of AR expression.

Conclusions:

AR can predict tamoxifen treatment benefit in patients with ER− tumours and triple-negative breast cancer.     

KRAS mutations detected by the amplification refractory mutation system-Scorpion assays strongly correlate with therapeutic effect of cetuximab

Background:

We aimed to compare the sensitive and quality-controlled KRAS testing with direct sequencing and to assess the impact on decision making of treatment.

Patients and methods:

We analysed genomic DNA isolated from macrodissected formalin-fixed paraffin-embedded specimens by direct sequencing and an amplification refractory mutation system–Scorpion assay (ARMS/S) method. Cetuximab was administered to patients identified as having wild-type (WT) KRAS using direct sequencing. Therapeutic effects were evaluated according to their KRAS status as determined by ARMS/S.

Results:

Among the 159 patients, the overall mutation rate was determined to be 37.0% by direct sequencing and 44.0% by ARMS/S. For the patients diagnosed as WT by direct sequencing and treated with cetuximab (n=47), a response rate of 16.0% was observed for 38 ARMS/S WT patients, whereas 9 ARMS/S mutant (MUT) patients failed to respond. The ARMS/S WT patients showed significant improvement in progression-free survival (PFS) and overall survival (OS) compared with ARMS/S MUT patients (PFS median 5.0 vs 1.7 months, hazards ratio (HR)=0.29, P=0.001; OS median 12.1 vs 3.8 months, HR=0.26, P=0.001).

Conclusion:

Sensitive and quality-controlled KRAS testing may provide improved predictive power to determine the efficacy of anti-epidermal growth factor antibodies.     

VeriStrat? has prognostic value in advanced stage NSCLC patients treated with erlotinib and sorafenib

Background:

The serum proteomic test VeriStrat has been shown to be able to classify advanced non-small cell lung cancer (NSCLC) patients for overall survival (OS) after treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). In this study, VeriStrat was evaluated as a pre-treatment stratification tool in patients with advanced stage NSCLC for treatment with the combination of erlotinib and sorafenib, considering both OS and progression-free survival (PFS) as end points.

Methods:

Serum samples from 50 patients treated within the context of a phase II trial of first-line erlotinib and sorafenib were analysed with VeriStrat, a fully locked mass spectrometry-based test that identifies patients likely to have good or poor outcome on EGFR therapy based on eight distinct features in mass spectra. Analysis was performed fully blinded to all clinical data, and then the outcome data were analysed with respect to the obtained serum classifications.

Results:

VeriStrat classified pre-treatment samples into two groups, VeriStrat Good and VeriStrat Poor, which were significantly different in OS (hazard ratio (HR) 0.30, log-rank P=0.009) and in PFS (HR 0.40, log-rank P=0.035).

Conclusion:

VeriStrat has shown its potential for stratification of unselected, advanced stage NSCLC patients treated in first line with a combination of erlotinib and sorafenib.     

Activation of the PI3K/AKT pathway correlates with prognosis in stage II colon cancer

Background:

Patients with UICC/AJCC stage II colon cancer have a high 5-year overall survival rate after surgery. Nevertheless, a significant subgroup of patients develops tumour recurrence. Currently, there are no clinically established biomarkers available to identify this patient group. We applied reverse-phase protein arrays (RPPA) for phosphatidylinositide-3-kinase pathway activation mapping to stratify patients according to their risk of tumour recurrence after surgery.

Methods:

Full-length proteins were extracted from formalin-fixed, paraffin-embedded tissue samples of 118 patients who underwent curative resection. RPPA technology was used to analyse expression and/or phosphorylation levels of six major factors of the phosphatidylinositide-3-kinase pathway. Oncogenic mutations of KRAS and BRAF, and DNA microsatellite status, currently discussed as prognostic markers, were analysed in parallel.

Results:

Expression of phospho-AKT (HR=3.52; P=0.032), S6RP (HR=6.3; P=0.044), and phospho-4E-BP1 (HR=4.12; P=0.011) were prognostic factors for disease-free survival. None of the molecular genetic alterations were significantly associated with prognosis.

Conclusions:

Our data indicate that activation of the PI3K/AKT pathway evidenced on the protein level might be a valuable prognostic marker to stratify patients for their risk of tumour recurrence. Beside adjuvant chemotherapy targeting of upregulated PI3K/AKT signalling may be an attractive strategy for treatment of high-risk patients.     

Concomitant oral tyrosine kinase inhibitors and bisphosphonates in advanced renal cell carcinoma with bone metastases

Background:

The presence of bone metastases in patients with metastatic renal cell carcinoma treated with oral tyrosine kinase inhibitors (TKIs) is associated with poorer outcome as compared with patients without bone involvement. Concomitant bisphosphonates could probably improve outcomes but also induce osteonecrosis of the jaw (ONJ).

Methods:

Retrospective study on all the renal cell carcinoma patients with bone metastases treated with sunitinib or sorafenib between November 2005 and June 2012 at the University Hospitals Leuven and AZ Groeninge in Kortrijk.

Results:

Seventy-six patients were included in the outcome analysis: 49 treated with concomitant bisphosphonates, 27 with TKI alone. Both groups were well balanced in terms of prognostic and predictive markers. Response rate (38% vs 16% partial responses, P=0.028), median progression-free survival (7.0 vs 4.0 months, P=0.0011) and median overall survival (17.0 vs 7.0 months, P=0.022) were significantly better in patients receiving bisphosphonates. The incidence of ONJ was 10% in patients treated with TKI and bisphosphonates.

Conclusion:

Concomitant use of bisphosphonates and TKI in renal cell carcinoma patients with bone involvement probably improves treatment efficacy, to be confirmed by prospective studies, but is associated with a high incidence of ONJ.     

Correlation of bevacizumab-induced hypertension and outcome in the BOXER study, a phase II study of capecitabine, oxaliplatin (CAPOX) plus bevacizumab as peri-operative treatment in 45 patients with poor-risk colorectal liver-only metastases unsuitable for upfront resection

Background:

Bevacizumab is commonly used in combination with chemotherapy in the treatment of metastatic colorectal cancer, but to date, despite extensive research, no predictive or prognostic biomarkers for bevacizumab have been identified. The development of bevacizumab-induced arterial hypertension has recently been suggested as a potential predictive biomarker.

Methods:

Blood pressure was recorded during the BOXER study, a phase II study of capecitabine, oxaliplatin (CAPOX) plus bevacizumab as peri-operative treatment in 45 patients with poor-risk colorectal liver-only metastases unsuitable for upfront resection. In this analysis, the development of bevacizumab-induced hypertension was correlated with clinical outcomes.

Results:

Fifteen percent of patients developed ⩾grade 1 hypertension while receiving neoadjuvant chemotherapy, and 4% developed grade 3 hypertension. There was no correlation between the development of hypertension and radiological response rate (P=0.642), progression-free survival (P=0.644) or overall survival (P=0.480) in those who developed hypertension compared with those who did not.

Conclusion:

Bevacizumab-induced hypertension did not predict radiological response or survival in our study. The results highlight a number of important issues regarding the use of hypertension as a biomarker.     

Prognostic and predictive value of common mutations for treatment response and survival in patients with metastatic colorectal cancer

Background:

We address the prognostic and predictive value of KRAS, PIK3CA and BRAF mutations for clinical outcomes in response to active agents in the treatment of metastatic colorectal cancer (mCRC).

Methods:

We determined KRAS, BRAF and PIK3CA mutations in tumours from 168 patients treated for mCRC at two institutions. All patients received 5-FU-based first-line chemotherapy and treatment outcome was analysed retrospectively.

Results:

KRAS, BRAF and PIK3CA mutations were present in 62 (37%), 13 (8%) and 26 (15%) cases, respectively. Multivariate analysis uncovered BRAF mutation as an independent prognostic factor for decreased survival (hazard ratio (HR) 4.0, 95% confidence interval (CI) 2.1–7.6). In addition, patients with BRAF-mutant tumours had significantly lower progression-free survival (PFS: HR 4.0, 95% CI 2.2–7.4) than those whose tumors that carried wild-type BRAF. Among 92 patients treated using chemotherapy and cetuximab as salvage therapy, KRAS mutation was associated with lack of response (P=0.002) and shorter PFS (P=0.09). BRAF (P=0.0005) and PIK3CA (P=0.01) mutations also predicted reduced PFS in response to cetuximab salvage therapy.

Conclusions:

These results underscore the potential of mutational profiling to identify CRCs with different natural histories or treatment responses. The adverse significance of BRAF mutation should inform patient selection and stratification in clinical trials.     

Effect of adjuvant trastuzumab among patients treated with anti-HER2-based neoadjuvant therapy

Purpose:

To study the impact of adjuvant trastuzumab among patients achieving a pathologic complete response (pCR) after trastuzumab-based neoadjuvant systemic therapy (NST).

Patients and methods:

Patients with primary HER2-positive breast cancer treated with trastuzumab-based NST were categorised according to adjuvant trastuzumab administration and pCR status. Adjuvant trastuzumab became standard of care in 2006, this was the main reason patients in our cohort did not receive adjuvant trastuzumab. Kaplan–Meier was used to estimate survival. A test for interaction between adjuvant trastuzumab and pCR was completed.

Findings:

Of 589 patients, 203 (34.5%) achieved a pCR. After surgery, 109 (18.5%) patients in the entire cohort did not receive adjuvant trastuzumab. Among patients achieving a pCR, 31.3% received adjuvant trastuzumab compared with 68.8% among those who did not achieve a pCR (P=0.0006). Among patients achieving pCR, adjuvant trastuzumab did not further improve overall survival (OS) or relapse-free survival (RFS) (P=0.35 and P=0.93, respectively). Any benefit of adjuvant trastuzumab in OS and RFS among patients without a pCR did not achieve statistical significance (P=0.3 and P=0.44, respectively).

Conclusions:

In this cohort, patients treated with trastuzumab-based NST who achieved a pCR have excellent outcome regardless of whether they received adjuvant trastuzumab.     

Changes in circulating microRNA-126 during treatment with chemotherapy and bevacizumab predicts treatment response in patients with metastatic colorectal cancer

Background:

This study investigated the predictive value of circulating microRNA-126 (cir-miRNA-126) in patients with metastatic colorectal cancer (mCRC) treated with first-line chemotherapy combined with bevacizumab.

Methods:

The study included 68 patients. Blood samples (plasma) were collected before the treatment initiation, at the first clinical evaluation after 3 weeks and at progression. Levels of cir-miRNA-126 were determined by qRT–PCR after purification of total RNA from plasma. Primary clinical end points were response rates evaluated according to the Response Evaluation Criteria In Solid Tumours (RECIST) and progression-free survival (PFS).

Results:

Changes in circulating miRNA-126 during treatment were predictive of tumour response. Non-responding patients had a median increase in cir-miRNA-126 of 0.244 (95% confidence interval (CI), 0.050–0.565) compared with a median decrease of −0.374 (95% CI, −0.472 to −0.111) in the responding patients, P=0.002. A significant positive correlation was demonstrated by comparing the changes in tumour size with the changes in cir-miRNA-126, r=0.48, P=0.0001. Grouping the patients according to the changes in cir-miRNA-126 disclosed a borderline significant separation of the groups in the PFS analysis favouring patients with decreasing miRNA-126 levels, hazard ratio (HR) 0.60 (95% CI, 0.33–1.09), P=0.07.

Conclusions:

The present results indicate that changes in cir-miRNA-126 during treatment are related to the response to chemotherapy and bevacizumab in patients with mCRC, thus representing a possible biomarker for the resistance to anti-angiogenic containing treatments.     

The impact of CYP2D6-predicted phenotype on tamoxifen treatment outcome in patients with metastatic breast cancer

Background:

Cytochrome P450 2D6 (CYP2D6) has a crucial role in the metabolic conversion of tamoxifen into the active metabolite endoxifen. In this cohort study, the effect of CYP2D6-predicted phenotype, defined as the combined effect of CYP2D6 genetic variation and concomitant use of CYP2D6-inhibiting medication, on time to breast cancer progression (TTP) and overall survival (OS) in women who use tamoxifen for metastatic breast cancer (MBC) was examined.

Methods:

We selected patients treated with tamoxifen (40 mg per day) for hormone receptor-positive MBC from whom a blood sample for pharmacogenetic analysis (CYP2D6*3, *4, *5, *6, *10 and *41) was available. Patient charts (n=102) were reviewed to assess TTP and OS, and to determine whether CYP2D6 inhibitors were prescribed during tamoxifen treatment.

Results:

OS was significantly shorter in patients with a poor CYP2D6 metaboliser phenotype, compared with extensive metabolisers (HR=2.09; P=0.034; 95% CI: 1.06–4.12). Co-administration of CYP2D6 inhibitors alone was also associated with a worse OS (HR=3.55; P=0.002; 95% CI: 1.59–7.96) and TTP (HR=2.97; P=0.008; 95% CI: 1.33–6.67) compared with patients without CYP2D6 inhibitors.

Conclusion:

CYP2D6 phenotype is an important predictor of treatment outcome in women who are receiving tamoxifen for MBC. Co-administration of CYP2D6 inhibitors worsens treatment outcome of tamoxifen and should therefore be handled with care.     

Cellular senescence predicts treatment outcome in metastasised colorectal cancer

Background:

Cellular senescence is a terminal cell-cycle arrest that occurs in response to activated oncogenes and DNA-damaging chemotherapy. Whether cancer cell senescence at diagnosis might be predictive for treatment outcome is unknown.

Methods:

A senescence index (SI) was developed and used to retrospectively correlate the treatment outcome of 30 UICC stage IV colorectal cancer (CRC) patients with their SI at diagnosis.

Results:

5-Fluorouracil/leucovorin-treated CRC patients achieved a significantly longer progression-free survival when presenting with SI-positive tumours before therapy (median 12.0 vs 6.0 months; P=0.044).

Conclusion:

Cancer cell senescence predicts treatment outcome in metastasised CRC. Prospective analyses of larger patient cohorts are needed.     

Nuclear receptor co-activators and HER-2/neu are upregulated in breast cancer patients during neo-adjuvant treatment with aromatase inhibitors

Background:

Acquired resistance to endocrine therapy in breast cancer is poorly understood. Characterisation of the molecular response to aromatase inhibitors in breast cancer tissue may provide important information regarding development of oestrogen hypersensitivity.

Methods:

We examined the expression levels of nuclear receptor co-regulators, the orphan nuclear receptor liver receptor homologue-1 and HER-2/neu growth factor receptor using real-time RT-PCR before and after 13–16 weeks of primary medical treatment with the aromatase inhibitors anastrozole or letrozole.

Results:

mRNA expression of the steroid receptor co-activator 1 (SRC-1) and peroxisome-proliferator-activated receptor γ co-activator-1α (PGC-1α) was correlated (P=0.002), and both co-activators increased during treatment in the patient group as a whole (P=0.008 and P=0.032, respectively), as well as in the subgroup of patients achieving an objective treatment response (P=0.002 and P=0.006). Although we recorded no significant change in SRC-3/amplified in breast cancer 1 level, the expression correlated positively to the change of SRC-1 (P=0.002). Notably, we recorded an increase in HER-2/neu levels during therapy in the total patient group (18 out of 26; P=0.016), but in particular among responders (15 out of 21; P=0.008).

Conclusion:

Our results show an upregulation of co-activator mRNA and HER-2/neu during treatment with aromatase inhibitors. These mechanisms may represent an early adaption of the breast cancer cells to oestrogen deprivation in vivo.     

Combination of letrozole,metronomic cyclophosphamide and sorafenib is well-tolerated and shows activity in patients with primary breast cancer

Purpose:

To assess whether the combination of letrozole, metronomic cyclophosphamide and sorafenib (LCS) is well tolerated and shows activity in primary breast cancer (BC).

Methods:

Thirteen oestrogen receptor-positive, postmenopausal, T2-4, N0-1 BC patients received the LCS combination for 6 months. In these patients we examined the pharmacokinetics of sorafenib and cyclophosphamide, toxicity of the regimen, the clinical response to therapy and changes in the levels of biologically relevant biomarkers.

Results:

Adequate plasma concentrations of sorafenib were achieved in patients when it was dosed in combination with L+C. The mean plasma concentrations of C were consistently lower following administration of LCS, compared with administration of L+C only. The most common drug-related grade 3/4 adverse events were skin rash (69.3%), hand-foot skin reaction (69.3%) and diarrhoea (46.1%). According to RECIST Criteria, a clinical complete response was observed in 6 of 13 patients. A significant reduction in tumour size, evaluated with MRI, was also observed between baseline and 14 days of treatment in all 13 patients (P=0.005). A significant reduction in SUV uptake, measured by ¹⁸FDG-PET/CT, was observed in all patients between baseline and 30 days of treatment (P=0.015) and between baseline and definitive surgery (P=0.0002). Using modified CT Criteria, a response was demonstrated in 8 out of 10 evaluable patients at 30 days and in 11 out of 13 evaluable patients at the definitive surgery. A significant reduction in Ki67 expression was observed in all patients at day 14 compared with baseline (P<0.00001) and in 9 out of 13 patients at the definitive surgery compared with baseline (P<0.03). There was also a significant suppression of CD31 and VEGF-A expression in response to treatment (P=0.01 and P=0.007, respectively).

Conclusions:

The LCS combination is feasible and tolerable. The tumour response and target biomarker modulation indicate that the combination is clinically and biologically active.     

Expression of EZH2 and Ki-67 in colorectal cancer and associations with treatment response and prognosis

Background:

Enhancer of zeste homologue 2 (EZH2) is a member of the Polycomb group of genes that is involved in epigenetic silencing and cell cycle regulation.

Methods:

We studied EZH2 expression in 409 patients with colorectal cancer stages II and III. The patients were included in a randomised study, and treated with surgery alone or surgery followed by adjuvant chemotherapy.

Results:

EZH2 expression was significantly related to increased tumour cell proliferation, as assessed by Ki-67 expression. In colon cancer, strong EZH2 expression (P=0.041) and high proliferation (⩾40%; P=0.001) were both associated with better relapse-free survival (RFS). In contrast, no such associations were found among rectal cancers. High Ki-67 staining was associated with improved RFS in colon cancer patients who received adjuvant chemotherapy (P=0.001), but not among those who were treated by surgery alone (P=0.087). In colon cancers stage III, a significant association between RFS and randomisation group was found in patients with high proliferation (P=0.046), but not in patients with low proliferation (P=0.26). Multivariate analyses of colon cancers showed that stage III (hazard ratio (HR) 4.00) and high histological grade (HR 1.80) were independent predictors of reduced RFS, whereas high proliferation indicated improved RFS (HR 0.55).

Conclusion:

Strong EZH2 expression and high proliferation are associated features and both indicate improved RFS in colon cancer, but not so in rectal cancer.