Prognostic value of histopathologic traits independent of stromal tumor-infiltrating lymphocyte levels in chemotherapy-naïve patients with triple-negative breast cancer.

BACKGROUND: In the absence of prognostic biomarkers, most patients with early-stage triple-negative breast cancer (eTNBC) are treated with combination chemotherapy. The identification of biomarkers to select patients for whom treatment de-escalation or escalation could be considered remains an unmet need. We evaluated the prognostic value of histopathologic traits in a unique cohort of young, (neo)adjuvant chemotherapy-naïve patients with early-stage (stage I or II), node-negative TNBC and long-term follow-up, in relation to stromal tumor-infiltrating lymphocytes (sTILs) for which the prognostic value was recently reported. MATERIALS AND METHODS: We studied all 485 patients with node-negative eTNBC from the population-based PARADIGM cohort which selected women aged <40 years diagnosed between 1989 and 2000. None of the patients had received (neo)adjuvant chemotherapy according to standard practice at the time. Associations between histopathologic traits and breast cancer-specific survival (BCSS) were analyzed with Cox proportional hazard models. RESULTS: With a median follow-up of 20.0 years, an independent prognostic value for BCSS was observed for lymphovascular invasion (LVI) [adjusted (adj.) hazard ratio (HR) 2.35, 95% confidence interval (CI) 1.49-3.69], fibrotic focus (adj. HR 1.61, 95% CI 1.09-2.37) and sTILs (per 10% increment adj. HR 0.75, 95% CI 0.69-0.82). In the sTILs <30% subgroup, the presence of LVI resulted in a higher cumulative incidence of breast cancer death (at 20 years, 58%; 95% CI 41% to 72%) compared with when LVI was absent (at 20 years, 32%; 95% CI 26% to 39%). In the ≥75% sTILs subgroup, the presence of LVI might be associated with poor survival (HR 11.45, 95% CI 0.71-182.36, two deaths). We confirm the lack of prognostic value of androgen receptor expression and human epidermal growth factor receptor 2 -low status. CONCLUSIONS: sTILs, LVI and fibrotic focus provide independent prognostic information in young women with node-negative eTNBC. Our results are of importance for the selection of patients for de-escalation and escalation trials.

Health-related quality of life analysis in stage III melanoma patients treated with adjuvant dendritic cell therapy.

BACKGROUND: Health-related quality of life (HRQoL) is an important issue in the rapidly evolving field of adjuvant treatment for stage III melanoma. Dendritic cell vaccination is one of the adjuvant forms of therapy currently investigated. METHODS: We enrolled adults with stage III melanoma to receive adjuvant dendritic cell vaccination after a complete radical lymph node dissection. HRQoL assessment was one of the secondary endpoints of this trial and investigated with the EORTC-QLQ-C30 questionnaire at baseline and week 26. RESULTS: Fifteen patients with a median age of 50 years were included in the study, with twelve evaluable patients on study at time of the second questionnaire. Global health status and role functioning improved clinically relevant with a mean difference of 15 (p = 0.010) and 26 points (p = 0.005), respectively. DISCUSSION: Despite the small number of patients, we found a clinically relevant improved global health status. Besides, compared to the other investigated therapies, toxicity of dendritic cell vaccination is low, which supports our finding. CONCLUSION: This is the first description of HRQoL in melanoma patients receiving dendritic cell vaccination. We show the expected improvement in global health status after surgical treatment of stage III melanoma. Thus, adjuvant dendritic cell vaccination does not seem to hamper this improvement, as shown in our small explorative study.

Histopathologisch onderzoek van mogelijke metastase.

Histopathological examination of possible metastasis; indispensable or diagnostic excess?

St. Gallen endocrine response classes predict recurrence rates over time.

BACKGROUND: In 2007 the St. Gallen consensus panel defined three endocrine response classes: highly endocrine responsive (ER-H), incomplete endocrine responsive (ER-I) and non-endocrine responsive tumours (ER-N). However, it is uncertain whether ER-I tumours are less responsive than ER-H tumours. We investigated whether recurrence rates vary over time between response classes. Additionally, we investigated the most predictive response class definition for tamoxifen benefit. PATIENTS AND METHODS: We recollected tumours from 646 patients who participated in a randomized trial of adjuvant tamoxifen vs. OBSERVATION: Estrogen receptor (ER), progesterone receptor (PgR), HER2 status and tumour grade were revised centrally. St. Gallen classes were evaluated for recurrence free interval (RFI). Change in hazards over time was assessed. Subsequently, 6 alternative response class definitions were compared to optimize the cut-off for PgR and ER. RESULTS: Schoenfeld residuals indicate a failure of proportional hazards between the endocrine response groups (p = 0.0001). The HR for recurrence risk shifted over time with the ER-H group initially being at lower risk (HR ER-H vs. ER-I 0.5), but after six years the recurrence risk increased (HR 1.9). The cut-off values for ER and PgR that statistically best discriminated RFI in the first 4 years for lymph node positive patients were ER ≥ 50% and PgR ≥ 75%. CONCLUSION: We demonstrated a marked variability in endocrine therapy benefit. Patients with ER-H tumours have a larger benefit during adjuvant tamoxifen and in the first years after accomplishing of the therapy, but suffer from late recurrences. This might have implications for optimal treatment duration.

Risk estimations and treatment decisions in early stage breast cancer: agreement among oncologists and the impact of the 70-gene signature.

BACKGROUND: Clinical decision-making in patients with early stage breast cancer requires adequate risk estimation by medical oncologists. This survey evaluates the agreement among oncologists on risk estimations and adjuvant systemic treatment (AST) decisions and the impact of adding the 70-gene signature to known clinico-pathological factors. METHODS: Twelve medical oncologists assessed 37 breast cancer cases (cT1-3N0M0) and estimated their risk of recurrence (high or low) and gave a recommendation for AST. Cases were presented in two written questionnaires sent 4 weeks apart. Only the second questionnaire included the 70-gene signature result. RESULTS: The level of agreement among oncologists in risk estimation (κ=0.57) and AST recommendation (κ=0.57) was 'moderate' in the first questionnaire. Adding the 70-gene signature result significantly increased the agreement in risk estimation to 'substantial' (κ=0.61), while agreement in AST recommendations remained 'moderate' (κ=0.56). Overall, the proportion of high risk was reduced with 7.4% (range: 6.9-22.9%; p<0.001) and the proportion of chemotherapy that was recommended was reduced with 12.2% (range: 5.4-29.5%; p<0.001). CONCLUSION: Oncologists' risk estimations and AST recommendations vary greatly. Even though the number of participating oncologists is low, our results underline the need for a better standardisation tool in clinical decision-making, in which integration of the 70-gene signature may be helpful in certain subgroups to provide patients with individualised, but standardised treatment.

Panitumumab monotherapy as a second-line treatment in metastasised colorectal cancer: a single centre experience.

AIMS: To report our clinical experience of panitumumab monotherapy as a second-line treatment for patients with metastatic colorectal cancer (mCRC). MATERIALS AND METHODS: This retrospective, descriptive study included a series of consecutive patients receiving panitumumab monotherapy (6 mg/kg 2 weekly) at a single centre in the Netherlands between June 2009 and November 2011. All patients had wild-type KRAS tumours, had progressed during first-line fluoropyrimidine-based therapy and were not candidates for, or refused, standard second-line therapy (usually irinotecan in the Netherlands). Prophylactic medication was given for epidermal growth factor receptor inhibitor-associated skin toxicities. RESULTS: Thirty-one patients were treated during this period. The most commonly administered first-line mCRC regimen was capecitabine/oxaliplatin/bevacizumab (18/31 patients; 58.1%). Patients received a mean of 7.9 (range 1-18) panitumumab cycles. The median progression-free survival was 3.4 (95% confidence interval 2.4, 4.4) months. The median overall survival estimates were 11.4 (95% confidence interval 1.2, 21.6) months from the initiation of panitumumab monotherapy. Ten patients experienced partial responses according to Response Evaluation Criteria In Solid Tumors (RECIST; objective response rate: 32.3%); disease was controlled (objective response or stable disease) in 15 patients (48.4%). Carcinoembryonic antigen (CEA) responses (two consecutive ≥10% decreases from baseline) occurred in 11/29 patients (37.9%); all of whom had >50% decreases in CEA levels. All patients with an objective response at week 12 had CEA reductions at weeks 6 and 12. The only adverse events were grade 1/2 skin toxicities (61.3%) and gastrointestinal complaints (6.5%); three other patients (9.7%) experienced both skin and gastrointestinal complaints. CONCLUSION: Panitumumab monotherapy seems to be a safe and active second-line treatment for patients with wild-type KRAS mCRC, with activity in line with that seen for irinotecan monotherapy, but with less toxicity. CEA may provide a useful early indicator of response to panitumumab.

CYP2C19 2 predicts substantial tamoxifen benefit in postmenopausal breast cancer patients randomized between adjuvant tamoxifen and no systemic treatment.

Estrogen catabolism is a major function of CYP2C19. The effect of CYP2C19 polymorphisms on tamoxifen sensitivity may therefore not only be mediated by a variation in tamoxifen metabolite levels but also by an effect on breast cancer risk and molecular subtype due to variation in lifelong exposure to estrogens. We determined the association between these polymorphisms and tamoxifen sensitivity in the context of a randomized trial, which allows for the discernment of prognosis from prediction. We isolated primary tumor DNA from 535 estrogen receptor-positive, stages I-III, postmenopausal breast cancer patients who had been randomized to tamoxifen (1-3 years) or no adjuvant therapy. Recurrence-free interval improvement with tamoxifen versus control was assessed according to the presence or absence of CYP2C19 2 and CYP2C19 17. Hazard ratios and interaction terms were calculated using multivariate Cox proportional hazard models, stratified for nodal status. Tamoxifen benefit was not significantly affected by CYP2C19 17. Patients with at least one CYP2C19 2 allele derived significantly more benefit from tamoxifen (HR 0.26; p = 0.001) than patients without a CYP2C19 2 allele (HR 0.68; p = 0.18) (p for interaction 0.04). In control patients, CYP2C19 2 was an adverse prognostic factor. In conclusion, breast cancer patients carrying at least one CYP2C19 2 allele have an adverse prognosis in the absence of adjuvant systemic treatment, which can be substantially improved by adjuvant tamoxifen treatment.

Additional value of the 70-gene signature and levels of ER and PR for the prediction of outcome in tamoxifen-treated ER-positive breast cancer.

BACKGROUND: Breast cancer patients with node positive disease can have an excellent outcome with tamoxifen only. It is unclear whether analysing both the 70-gene signature and hormone receptors provides superior prediction of outcome in tamoxifen-treated patients than either alone. METHODS: Three series were evaluated: 121 patients (81% node positive) received adjuvant tamoxifen, 151 patients did not receive tamoxifen (10% node positive) and 92 patients received tamoxifen for metastatic disease. The 70-gene signature was analysed using MammaPrint. Oestrogen receptor (ER) and progesterone receptor (PR) immunohistochemistry was evaluated following St. Gallen Consensus (Highly Endocrine Responsive: ER and PR ≥ 50%, Incompletely Endocrine Responsive: ER and/or PR low or either one absent). RESULTS: In patients treated with adjuvant tamoxifen, both the 70-gene signature (adjusted for Endocrine Response Categories HR 2.17, 95%CI 1.01-4.66) as well as the Endocrine Response Categories (adjusted for 70-gene signature HR 6.35, 95%CI 1.90-21.3) were associated with breast-cancer-specific-survival (BCSS). Also in patients treated with tamoxifen for metastatic disease, combined analysis of the 70-gene signature and ER/PR revealed additional value (multivariate Cox regression, p = 0.013). In patients who did not receive tamoxifen, only the 70-gene signature was associated with outcome. CONCLUSION: In the series analysed, the 70-gene signature was mainly a prognostic factor, while ER and PR levels were mainly associated with outcome after tamoxifen. Combination of these three factors may improve outcome prediction in tamoxifen-treated patients.

Development and validation of a quantitative assay for the analysis of tamoxifen with its four main metabolites and the flavonoids daidzein, genistein and glycitein in human serum using liquid chromatography coupled with tandem mass spectrometry.

The development and validation of a bioanalytical assay is described for the simultaneous analysis in human serum of tamoxifen, four of its main metabolites and three flavonoids, which are known constituents in alternative medicine and dietary supplements often used by breast cancer patients. The method has been fully validated at linear ranges covering steady-state serum concentrations in patients who receive therapeutic dosages of tamoxifen. The wide range also allows for quantification of large inter-patient fluctuations of flavonoid concentrations. The bioanalytical assay is based on reversed phase liquid chromatography coupled with tandem mass spectrometry in the positive ion mode using multiple reaction monitoring for drug (-metabolite) quantification. The sample pretreatment consists of a protein precipitation with acetonitrile using only 50 microL serum. The described method is simple, robust and reproducible with inter- and intra-assay accuracies within 85-115%. The applicability of the assay was demonstrated and it is now successfully used to study the in vivo pharmacokinetics of tamoxifen, its main metabolites and flavonoids in human serum of patients receiving tamoxifen.

Phosphorylation of the oestrogen receptor alpha at serine 305 and prediction of tamoxifen resistance in breast cancer.

Phosphorylation of oestrogen receptor alpha at serine 305 (ERalphaS305-P) induces tamoxifen resistance in experimental studies, but does not influence response to other endocrine agents, such as fulvestrant. We evaluated ERalphaS305-P using immunohistochemistry in 377 breast carcinomas from premenopausal participants of a randomized trial (n=248) and patients with advanced disease (n=129). Among the premenopausal patients, adjuvant tamoxifen improved recurrence-free survival (RFS) for ERalphaS305-P-negative tumours (multivariate HR=0.53, 95% CI 0.32-0.86, p=0.010), but not for ERalphaS305-P-positive tumours (multivariate HR=1.01, 95% CI 0.33-3.05, p=0.99) (interaction p=0.131). Notably, ERalphaS305-P was not significantly associated with RFS in patients not treated with tamoxifen (multivariate HR=0.64, 95% CI 0.30-1.37, p=0.248), indicating that ERalphaS305-P is a marker for treatment outcome rather than tumour progression. Given the direct experimental link between ERalphaS305-P and tamoxifen resistance and these first clinical data suggesting that premenopausal patients with ERalphaS305-P-positive breast cancer are resistant to adjuvant tamoxifen, further research is encouraged to study whether alternative endocrine treatment should be considered for this subgroup.