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

BackgroundClinical 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.MethodsTwelve 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.ResultsThe 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).ConclusionOncologists’ 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.     

The 70-gene prognosis signature predicts early metastasis in breast cancer patients between 55 and 70 years of age

BackgroundThe majority of breast cancer patients are postmenopausal women who are increasingly being offered adjuvant chemotherapy. Since the beneficial effect of chemotherapy in postmenopausal patients predominantly occurs in the first 5 years after diagnosis, a prognostic marker for early events can be of use for adjuvant treatment decision making. The aim of this study was to evaluate the prognostic value of the 70-gene prognosis signature for early events in postmenopausal patients.MethodsFrozen tumor samples from 148 patients aged 55–70 years were selected (T1–2, N0) and classified by the 70-gene prognosis signature (MammaPrint™) into good or poor prognosis. Eighteen percent received hormonal therapy.ResultsBreast cancer-specific survival (BCSS) at 5 years was 99% for the good-prognosis signature versus 80% for the poor-prognosis signature group (P = 0.036). The 70-gene prognosis signature was a significant and independent predictor of BCCS during the first 5 years of follow-up with an adjusted hazard ratio of 14.4 (95% confidence interval 1.7–122.2; P = 0.01) at 5 years.ConclusionThe 70-gene prognosis signature can accurately select postmenopausal patients at low risk of breast cancer-related death within 5 years of diagnosis and can be of clinical use in selecting postmenopausal women for adjuvant chemotherapy.     

Prospective cost-effectiveness analysis of genomic profiling in breast cancer

BackgroundThe cost-effectiveness of the 70-gene signature (70-GS) (MammaPrint®) has earlier been estimated using retrospective validation data. Based on the prospective 5-year survival data of the microarRAy-prognoSTics-in-breast-cancER (RASTER) study, the aim here was to evaluate the cost-effectiveness reflecting the actual use in clinical practice, including reality-based compliance rates.MethodsCosts and outcomes (quality-adjusted-life-years (QALYs)) were calculated in node-negative (N?) patients included in the RASTER study (n = 427). Sensitivity and specificity of the 70-gene and Adjuvant! Online (AO) were based on 5-year distant-disease-free survival (DDFS). Subgroup analyses were performed for two groups for whom benefit of the 70-gene had earlier been reported: (1) ductal, oestrogen receptor-positive (ER+), tumour diameter 10–30 mm, grade II, age 40–70; (2) ductal, oestrogen receptor-positive, tumour diameter 5–30 mm, grade II/III and age 40–70.ResultsBased on 5-year survival data, the cost-effectiveness of the 70-gene signature versus AO was prospectively confirmed. The total health care costs per patient were €26,786 for the 70-gene and €29,187 for AO. The quality adjusted life years yielded 12.49 and 11.88, respectively. The subgroups retrieved slightly higher life gains and higher costs, but all resulted finally in a favourable position for the 70-gene signature.ConclusionsThe use of the 70-gene signature, as judged appropriate by doctors and patients and supported by a low risk 70-gene signature as an oncological safe choice, was also found to be cost-effective.     

Validation of the Complexity INdex in SARComas prognostic signature on formalin-fixed,paraffin-embedded,soft-tissue sarcomas

BackgroundPrediction of metastatic outcome in sarcomas is challenging for clinical management since they are aggressive and carry a high metastatic risk. A 67-gene expression signature, the Complexity INdex in SARComas (CINSARC), has been identified as a better prognostic factor than the reference pathological grade. Since it cannot be applied easily in standard laboratory practice, we assessed its prognostic value using nanoString on formalin-fixed, paraffin-embedded (FFPE) blocks to evaluate its potential in clinical routine practice and guided therapeutic management.MethodsA code set consisting of 67 probes derived from the 67 genes of the CINSARC signature was built and named NanoCind®. To compare the performance of RNA-seq and nanoString (NanoCind®), we used expressions of various sarcomas (n = 124, frozen samples) using both techniques and compared predictive values based on CINSARC risk groups and clinical annotations. We also used nanoString on FFPE blocks (n = 67) and matching frozen and FFPE samples (n = 45) to compare their level of agreement. Metastasis-free survival and agreement values in classification groups were evaluated.ResultsCINSARC strongly predicted metastatic outcome using nanoString on frozen samples (HR = 2.9, 95% CI: 1.23–6.82) with similar risk-group classifications (86%). While more than 50% of FFPE blocks were not analyzable by RNA-seq owing to poor RNA quality, all samples were analyzable with nanoString. When similar (risk-group) classifications were measured with frozen tumors (RNA-seq) compared with FFPE blocks (84% agreement), the CINSARC signature was still a predictive factor of metastatic outcome with nanoString on FFPE samples (HR = 4.43, 95% CI: 1.25–15.72).ConclusionCINSARC is a material-independent prognostic signature for metastatic outcome in sarcomas and outperforms histological grade. Unlike RNA-seq, nanoString is not influenced by the poor quality of RNA extracted from FFPE blocks. The CINSARC signature can potentially be used in combination with nanoString (NanoCind®) in routine clinical practice on FFPE blocks to predict metastatic outcome.     

Molecular classification of pulmonary sarcomatoid carcinomas suggests new therapeutic opportunities

BackgroundPulmonary sarcomatoid carcinoma (SC) is a rare disease with poor prognosis and with strong inter- and intratumor heterogeneity. However, molecular classification is currently focused on activating MET mutations. We sought to better characterize the molecular diversity of SC using mutational signatures that reflect different mutational processes, such as tobacco-associated adducts (signature 4), BRCA1/BRCA2 deficiency (signature 3), or APOBEC enzyme deamination (signatures 2 and 13).Patients and methodsWhole-exome sequencing was carried out in 15 SC patients and on data from 10 previously published cases. Hierarchical clustering and consensus non-negative matrix factorization were carried out for samples classification based on mutational signatures.ResultsIn the two series, SC distributed between two clusters (C): C_sig4 (characterized by signature 4) and C_{sig2–3–13} (signatures 2, 3, and 13). C_sig4 exhibited more frequent MAPK pathway mutations than C_{sig2–3–13} (pooled series: n = 10/14 versus 2/11, P < 0.05, respectively) and stronger PD-L1 expression (our series: n = 6/9 versus 1/6, P = 0.12). MET alterations were only found in C_{sig2–3–13} (pooled series: n = 5/11 versus 0/14, P = 0.009), as well as BRCA1/BRCA2 (n = 3/11 versus 0/15), EGFR (n = 1), and IDH1 (n = 1) mutations. C_{sig2–3–13} patients had better overall survival than C_sig4 patients (median: >45 versus 7 months, respectively, P = 0.001).ConclusionsOur study suggests that SC presents at least two clusters comprising different mutational processes, gene alterations, and PD-L1 expression. New potential treatment possibilities are immune checkpoint inhibitors in C_sig4 and specific targeted agents in C_{sig2–3–13}. These findings should encourage clinicians to conduct broad molecular and immunological testing in SC patients beyond MET exon 14 alterations.     

Class III β-tubulin,but not ERCC1, is a strong predictive and prognostic marker in locally advanced head and neck squamous cell carcinoma

BackgroundRecent researches revealed that class III β-tubulin (TUBB3) is a prognostic marker in various tumors and role of TUBB3 in head and neck squamous cell carcinoma (HNSCC) is not defined yet. We analyzed the significance of TUBB3 expression along with p53 and ERCC1 in locally advanced HNSCC patients receiving cisplatin-based induction chemotherapy.Materials and methodsRetrospective review of medical records at Seoul National University Hospital between 1998 and 2007 was carried out. Immunohistochemical stain of TUBB3, p53, and ERCC1 was done in paraffin-embedded tumor tissue. We assessed response to treatment, progression-free survival (PFS), overall survival (OS), and cancer-specific survival (CSS).ResultsEighty-five patients with oropharyngeal, hypopharyngeal, and laryngeal cancers received induction chemotherapy with 5-fluorouracil (5-FU) and cisplatin (n = 55), or 5-FU, cisplatin, and docetaxel (Taxotere) (n = 30). Eighty-three received definitive treatment after induction chemotherapy, where 62 received radiotherapy and 21 received surgery. TUBB3-positive patients showed lower response rate than TUBB3-negative patients (69% versus 88%, P = 0.039). Shorter median PFS was observed in TUBB3-positive group (12 versus 47 months, P = 0.001). Shorter median OS was observed in TUBB-positive group not reaching statistical significance (30 versus 59 months, P = 0.072). TUBB3 status significantly influenced CSS (35 months versus not reached, P = 0.017). Positive p53 status was related to poorer OS and CSS. ERCC1 showed no influence on chemotherapy response, PFS, OS, and CSS.ConclusionTUBB3 is a predictive and prognostic marker along with well-known p53 in HNSCC patients receiving cisplatin-based induction chemotherapy. Clinical impact of ERCC1 is not evident in this setting.     

Tumour budding is a strong and independent prognostic factor in pancreatic cancer

IntroductionPancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer that escapes detection and resists treatment. Tumour budding, defined as the presence of de-differentiated single tumour cells or small cell clusters at the invasive front of gastrointestinal carcinomas like colorectal, oesophageal, gastric and ampullary, is linked to adverse prognosis. Tumour budding has not yet been reported in PDAC.AimTo assess the frequency and prognostic impact of tumour budding in PDAC.MethodsWhole-tissue sections of 117 PDACs with full clinico-pathological and follow-up information, including postoperative therapy, were stained using a pancytokeratin marker. Tumour budding was assessed in 10 high-power fields (HPFs) by two pathologists. High-grade budding was defined as an average of >10 buds across 10 HPFs. Measurements were correlated to patient and tumour characteristics. The study was performed according to the REMARK guidelines.ResultsInter-observer agreement was considered strong (ICC = 0.72). Low-grade budding was observed in 29.7% and high-grade budding in 70.3% cases. High-grade budding was linked to advanced pT classification (p = 0.0463), lymphatic invasion (p = 0.0192) and decreased disease-free (p = 0.0005) and overall survival (p < 0.0001). There was no association with pN, pM, R-status or blood vessel invasion. In multivariate analysis, the prognostic effect of tumour budding was independent of lymph node metastasis, lymphatic invasion and R-status (p < 0.0001; HR (95% CI): 3.65 (2.1–6.4)).ConclusionsOur results show that high-grade tumour budding occurs frequently in PDAC and is a strong, independent and reproducible, highly unfavourable prognostic factor that could be used to guide future individualised therapeutic approaches.     

Impact of early tumour shrinkage and resection on outcomes in patients with wild-type RAS metastatic colorectal cancer

BackgroundTumour shrinkage (TS) increases the possibility of resection in metastatic colorectal cancer (mCRC) and may improve tumour-related symptoms. Here we report prespecified secondary response–related end-points and exploratory TS/resection outcomes for patients with RAS wild-type (WT) tumours (no mutations in KRAS/NRAS exons 2/3/4) from the PRIME study (NCT00364013).MethodsPRIME was a randomised phase 3 study comparing first-line panitumumab + FOLFOX4 versus FOLFOX4 in mCRC patients. Tumour response analyses were conducted to compare response rates and their impact on survival outcomes.ResultsOverall, 505 patients had RAS WT mCRC. More patients receiving panitumumab + FOLFOX4 versus FOLFOX4 had ⩾30% (59% versus 38%; P < 0.001) or ⩾20% (72% versus 57%; P < 0.001) TS at week 8 (early TS); consistent TS benefits were observed over the first ∼40 weeks of treatment. Objective response rate (P = 0.003), duration of response (P = 0.0027), depth of response (P = 0.0149), progression-free survival (PFS; P = 0.0015) and overall survival (OS; P = 0.0057) were improved in the panitumumab + FOLFOX4 group. Both early TS and resection were associated with improved PFS and OS. 2-year OS rates for patients who did (n = 64) versus did not (n = 441) undergo resection were 88% versus 40%; 2-year OS rates for patients who did (n = 45) versus did not (n = 460) undergo complete resection were 96% versus 41%.ConclusionsMore patients receiving panitumumab + FOLFOX4 versus FOLFOX4 had ⩾30% or ⩾20% TS at week 8; PFS and OS were also improved with panitumumab + FOLFOX4. The clinical value of achieving early TS in mCRC warrants further investigation.     

Association between dietary folate intake and clinical outcome in head and neck squamous cell carcinoma

BackgroundThe association between dietary folate intake, two polymorphisms in methylenetetrahydrofolate reductase (MTHFR) and thymidylate synthase (TYMS), and survival in head and neck squamous cell carcinoma (HNSCC) patients is not clarified.Patients and methodsWe conducted a retrospective cohort study of 437 HNSCC patients treated at Aichi Cancer Center. We evaluated the survival impact of pretreatment dietary folate intake, which was estimated using a food-frequency questionnaire, and two polymorphisms, MTHFR C677T and a 6-bp insertion/deletion in the 3′-untranslated region of TYMS, using multivariate proportional hazard models.ResultsPatients with high folate intake (≥320 μg/day; n = 144) had significantly higher survival than patients with low or medium folate intake (<320 μg/day; n = 278; 79.1% versus 68.2%, respectively, P = 0.020). This association was consistent with multivariate analyses adjusted for established prognostic factors (hazard ratio 0.56; 95% confidence interval 0.37–0.84). MTHFR and TYMS polymorphisms did not show significant association with survival, although the TYMS 6-bp insertion allele showed potential association with a reduced risk of death. Notably, no significant interaction was observed between folate intake and the two examined polymorphisms.ConclusionsHigh pretreatment dietary folate intake was identified as an independent prognostic factor associated with improved clinical outcomes in HNSCC patients. Further study is warranted.     

Comparison of dosimetric parameters and acute toxicity of intensity-modulated and three-dimensional radiotherapy in patients with cervix carcinoma: A randomized prospective study

PurposeThe use of intensity-modulated radiotherapy (IMRT) to treat cervix carcinoma has increased, however prospective randomized trials are still lacking.AimTo compare the dosimetric parameters and associated acute toxicity in patients with cervix carcinoma treated with three-dimensional (3D) conformal radiotherapy and IMRT.Patients and methodsForty patients were randomized in two arms each consisting of 20 patients. Patients in both arms received concurrent chemoradiation (cisplatin 40 mg/m² weekly; 50 Gy/25 fractions). Patients were treated with 3D conformal radiotherapy in one arm and with IMRT in another arm. After external beam radiotherapy, all patients received brachytherapy (21 Gy/3 fractions at weekly interval). For dosimetric comparison, both kinds of the plans were done for all the patients. All patients were assessed throughout and until 90 days after completion of treatment for acute gastrointestinal, genitourinary and hematologic toxicities.ResultsBoth plans achieved adequate planning target volume coverage, while mean conformity index was found significantly better in IMRT plans (P-value = 0.001). D₃₅ (dose to 35% volume) and D₅₀ for bladder was reduced by 14.62 and 32.57% and for rectum by 23.82 and 43.68% in IMRT. For IMRT, V₄₅ (volume receiving 45 Gy) of bowel were found significantly lesser (P-value = 0.0001), non-tumour integral dose was found significantly higher (P-value = 0.0240) and V₂₀ of bone marrow was found significantly reduced (P-value = 0.019) in comparison to that in 3D conformal radiotherapy. Significant reduction of grade 2 or more (20 vs 45%; P-value = 0.058) and grade ≥ 3 (5 vs 15%, P-value = 0.004) acute genitourinary toxicity and grade 2 or more (20 vs 45%, P-value = 0.003) and grade 3 or more (5 vs. 20%, P-value = 0.004) acute gastrointestinal toxicity while no significant difference for grade 2 and 3 or more haematological toxicity was noted in patients treated with IMRT compared to 3D conformal radiotherapy.ConclusionIMRT provide a good alternative for treatment of cervix carcinoma with lower acute gastrointestinal and acute genitourinary toxicity with similar target coverage compared to 3D conformal radiotherapy.     

Expression of nuclear FIH independently predicts overall survival of clear cell renal cell carcinoma patients

AimThe hypoxia inducible factor (HIF) pathway plays an important role in sporadic clear cell renal cell carcinoma (ccRCC) by stimulating processes of angiogenesis, cell proliferation, cell survival and metastases formation. Herein, we evaluate the significance of upstream proteins directly regulating the HIF pathway; the prolyl hydroxylases domain proteins (PHD)1, 2 and 3 and factor-inhibiting HIF (FIH), as prognostic markers for ccRCC.MethodsImmunohistochemical marker expression was examined on a tissue microarray containing tumour tissue derived from 100 patients who underwent nephrectomy for ccRCC. Expression levels of HIF, FIH and PHD1, 2 and 3 were correlated with overall survival (OS) and clinicopathological prognostic factors.ResultsHIF-1α was positively correlated with HIF-2α (p < 0.0001), PHD1 (p = 0.024), PHD2 (p < 0.0001), PHD3 (p = 0.004), FIH (p < 0.0001) and VHL (p = 0.031). HIF-2α levels were significantly associated with FIH (p < 0.0001) and PHD2 (p = 0.0155). Mutations in the VHL gene, expression variations of HIF-1α, HIF-2α and PHD1, 2, 3 did not show a correlation to OS or clinicopathological prognostic factors. Tumour stage, grade, diameter, metastastic disease and intensity of nuclear FIH were significantly correlated to OS in univariable analysis (p = 0.023). Low nuclear FIH levels remained a strong independent prognostic factor in multivariable analysis (p = 0.009).ConclusionThese results show that low nuclear expression of FIH is a strong independent prognostic factor for a poor overall survival in ccRCC.     

Nephroureterectomy and segmental ureterectomy in the treatment of invasive upper tract urothelial carcinoma: A population-based study of 2299 patients

PurposeThe TNM staging system represents the cornerstone for classifying patients with upper tract urothelial carcinoma (UTUC). We tested the prognostic impact of pT and pN stages on cancer-specific mortality (CSM) in a large population-based cohort of surgically treated patients with UTUC.MethodsOur analyses relied on 2299 patients treated with nephroureterectomy (NU) or segmental ureterectomy (SU) for UTUC within nine Surveillance, Epidemiology and End Results registries between 1988 and 2004. CSM rates after surgery were graphically explored using Kaplan–Meier plots. Univariable and multivariable Cox regression models tested the effect of pT and pN stages on CSM, after adjusting for tumour grade, age, gender, primary tumour location, type and year of surgery.ResultsFive years after surgery, the overall CSM-free survival rate was 77.6%. The 5-year CSM-free survival rates of pT₁N₀ (n = 739), pT₂N₀ (n = 422), pT₃N₀ (n = 691), pT₄N₀ (n = 190) and any T N_1–3 (n = 257) were, respectively, 93.5 versus 86.2 versus 64.5 versus 54.7 versus 35.0%. The 5-year CSM-free survival rates of pT_1–2N_1–3 (n = 41) and pT_3–4N_1–3 (n = 216) patients were, respectively, 68.9% and 28.7% (p = 0.006). In multivariable analyses, pT and pN stages (p < 0.001), as well as tumour grade (p < 0.001), achieved independent predictor status. Advanced age adversely affected CSM-free survival (p = 0.001). Conversely, tumour location, gender, year and type of surgery did not exert independent predictor status.ConclusionDurable cancer control can be expected in patients treated with NU or SU for organ-confined (pT_1–2) UTUC. Conversely, the presence of non-organ-confined (pT_3–4) disease and/or of nodal metastases (pN_1–3) exerts a profound detrimental effect on CSM-free survival.     

Circulating Tumour Cells in locally advanced head and neck cancer: Preliminary report about their possible role in predicting response to non-surgical treatment and survival

Background and purposeThe mechanism of dissemination of locally advanced head and neck cancer (LAHNC) is far to be resolved. Circulating Tumour Cells (CTC) have been identified as a prognostic factor in metastatic breast and prostate cancer. This prospective multi-centric analysis studied the possible role of CTC identification in LAHNC.Materials and methodsCTC were searched in 73 patients with LAHNC (oropharynx, n = 39; nasopharynx, n = 10; larynx, n = 10; paranasal sinuses, n = 6, of whom 3 with sinonasal undifferentiated carcinoma, SNUC; hypopharynx, n = 5; oral cavity, n = 3). All of them (apart from SNUC) had squamous cell cancers. The relationship between CTC positivity and other clinical prognostic factors has been investigated. Response to treatment and survival has been related with changes in CTC number during the treatment.ResultsCTC were frequently identified in oro- and hypopharyngeal cancer and in SNUC. They were more frequent in stage IV than in stages I–III disease (18% versus 6%, p = NS (not significant)). Partial or complete response (CR) was related with the absence or disappearance of CTC during treatment (p = 0.017). A decrease in the CTC number or their absence throughout the treatment seems also related with non-progressive disease, after both complete or incomplete remission and with the proportion of patients alive and NED (no evidence of disease) (p = 0.009).ConclusionsThese preliminary data suggest a possible role of CTC determination in head and neck cancer. Additional and longer follow up data need to be collected to confirm these findings.     

First-line anthracycline-based chemotherapy for angiosarcoma and other soft tissue sarcoma subtypes: Pooled analysis of eleven European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group trials

BackgroundAngiosarcoma is a rare subtype of soft tissue sarcoma (STS). Doxorubicin is the standard first-line chemotherapy for advanced STS. It is not known whether angiosarcoma response to anthracycline-based chemotherapy is different to other STS subtypes.MethodsPooled data were analysed from 11 prospective randomised and non-randomised European Organisation for Research and Treatment of Cancer (EORTC) clinical trials of first-line anthracycline-based chemotherapy for advanced STS. Baseline patient characteristics, chemotherapy response, progression free survival (PFS) and overall survival (OS) of angiosarcoma patients were compared with other STS patients. Analysis was performed to identify factors prognostic for angiosarcoma response to chemotherapy, PFS and OS.ResultsWith a median follow-up of 4.2 years, data from 108 locally advanced and metastatic angiosarcoma patients and 2557 patients with other STS histologies were analysed. 25% of angiosarcoma patients had a complete or partial response to chemotherapy compared to 21% for other STS histotypes. The median PFS was 4.9 months and OS 9.9 months, which were not significantly different from other STS histotypes. In univariate analysis, bone metastases were an adverse prognostic factor for OS (hazard ratio (HR) 1.66, 95% confidence interval (CI) 1.03–2.67; p = 0.036). Tumour grade was as an adverse prognostic factor for PFS (HR 1.72, 95% CI 1.01–2.92; p = 0.044) and OS (HR 2.03; 95% CI 1.16–3.56; p = 0.011). Compared to single agent anthracyclines, doxorubicin + ifosfamide was associated with improved PFS (HR 0.53, 95% CI 0.33–0.86; p = 0.010) and OS (HR 0.53, 95% CI 0.32–0.90; p = 0.018).ConclusionsAngiosarcoma response and survival following first-line anthracycline-based chemotherapy was similar to other STS histotypes. Our analysis provides a useful measure of angiosarcoma response to chemotherapy for comparison with future clinical trials.     

Gene expression test for the non-invasive diagnosis of bladder cancer: A prospective,blinded, international and multicenter validation study

ObjectiveThis study aimed to validate, in a prospective, blinded, international and multicenter cohort, our previously reported four non-invasive tests for bladder cancer (BC) diagnosis based on the gene expression patterns of urine.MethodsConsecutive voided urine samples from BC patients and controls were prospectively collected in five European centres (n = 789). Finally, 525 samples were successfully analysed. Gene expression values were quantified using TaqMan Arrays and previously reported diagnostic algorithms were applied to gene expression data. Results from the most accurate gene signature for BC diagnosis were associated with clinical parameters using analysis of variance test.ResultsHigh diagnostic accuracy for the four gene signatures was found in the independent validation set (area under curve [AUC]=0.903–0.918), with the signature composed of two genes (GS_D2) having the best performance (sensitivity: 81.48%; specificity: 91.26%; AUC: 0.918). The diagnostic accuracy of GS_D2 was not affected by the number of tumours (p = 0.58) but was statistically associated with tumour size (p = 0.008). Also, GS_D2 diagnostic accuracy increases with increasing BC tumour risk. We found no differences in the performance of the GS_D2 test among the populations and centres in detecting tumours (p = 0.7) and controls (p = 0.2).ConclusionsOur GS_D2 test is non-invasive, non-observer dependent and non-labour-intensive, and has demonstrated diagnostic accuracy in an independent, international and multicenter study, equal or superior to the current gold standard (cystoscopy combined with cytology). Additionally, it has higher sensitivity than cytology while maintaining its specificity. Consequently, it meets the requirements for consideration as a molecular test applicable to clinical practice in the management of BC.     

Combined pathologic‐genomic algorithm for early-stage breast cancer improves cost-effective use of the 21-gene recurrence score assay

BackgroundThe 21-gene recurrence score (RS) (Oncotype DX®; Genomic Health, Redwood City, CA) partitions hormone receptor positive, node negative breast cancers into three risk groups for recurrence. The Anne Arundel Medical Center (AAMC) model has previously been shown to accurately predict RS risk categories using standard pathology data. A pathologic‐genomic (P-G) algorithm then is presented using the AAMC model and reserving the RS assay only for AAMC intermediate-risk patients.Patients and methodsA survival analysis was done using a prospectively collected institutional database of newly diagnosed invasive breast cancers that underwent RS assay testing from February 2005 to May 2015. Patients were assigned to risk categories based on the AAMC model. Using Kaplan–Meier methods, 5-year distant recurrence rates (DRR) were evaluated within each risk group and compared between AAMC and RS-defined risk groups. Five-year DRR were calculated for the P-G algorithm and compared with DRR for RS risk groups and the AAMC model’s risk groups.ResultsA total of 1268 cases were included. Five-year DRR were similar between the AAMC low-risk group (2.7%, n = 322) and the RS < 18 low-risk group (3.4%, n = 703), as well as between the AAMC high-risk group (22.8%, n = 230) and the RS > 30 high-risk group (23.0%, n = 141). Using the P-G algorithm, more patients were categorized as either low or high risk and the distant metastasis rate was 3.3% for the low-risk group (n = 739) and 24.2% for the high-risk group (n = 272). Using the P-G algorithm, 44% (552/1268) of patients would have avoided RS testing.ConclusionsAAMC model is capable of predicting 5-year recurrences in high- and low-risk groups similar to RS. Further, using the P-G algorithm, reserving RS for AAMC intermediate cases, results in larger low- and high-risk groups with similar prognostic accuracy. Thus, the P-G algorithm reliably identifies a significant portion of patients unlikely to benefit from RS assay and with improved ability to categorize risk.     

Ovarian Sertoli Leydig cell tumours in children and adolescents: An analysis of the European Cooperative Study Group on Pediatric Rare Tumors (EXPeRT)

ObjectiveTo analyse ovarian Sertoli-Leydig cell tumours (SLCTs) for potential prognostic markers and their use for treatment stratification.PatientsForty-four patients were included. Patients were prospectively reported to the German MAKEI (Maligne Keimzelltumoren) studies (n = 23), French TGM protocols (n = 10), Italian Rare Tumour Project (TREP) registry (n = 6), and the Polish Pediatric Rare Tumour Study group (n = 5). Tumours were classified according to World Health Organisation (WHO) and staged according to International Federation of Gynecological Oncology (FIGO).ResultsMedian age was 13.9 (0.5–17.4) years. All patients underwent resection by tumour enucleation (n = 8), ovariectomy (n = 17), adenectomy isolated (n = 18) or with hysterectomy (n = 1). FIGO-stage: Ia 24 pts., Ic 17 pts., II/III 3 pts. One patient had bilateral tumours. Four patients (stage Ia: 3, stage Ic: 1) developed a metachronous contralateral tumour. Otherwise, all stage Ia patients remained in complete remission. Among 20 patients with incomplete resection or tumour spread (stage Ic–III), eight relapsed, and five patients died. Eleven patients were initially treated with two to six cycles of cisplatin-based chemotherapy. Of these, seven patients are in continuous remission. Poor histological differentiation was associated with higher relapse rate (5/13) compared to intermediate (3/18) and high differentiation (0/4). Tumours with retiform pattern or heterologous elements showed a high relapse rate, too (5/11). After a median follow-up of 62 months, event-free survival is 0.70 ± 0.07, relapse-free survival 0.81 ± 0.06 and overall survival 0.87 ± 0.05.ConclusionsPrognosis of SLCTs is determined by stage and histopathologic differentiation. Complete resection with careful avoidance of spillage is a prerequisite of cure. The impact of chemotherapy in incompletely resected and advanced stage tumours remains to be evaluated.     

Patterns of care in older patients with squamous cell carcinoma of the head and neck: A Surveillance,Epidemiology, and End Results-Medicare analysis

BackgroundThere is growing evidence in the literature that older patients may not benefit from more intensive therapy for head and neck squamous cell carcinoma (HNSCC). A growing number of patients with HNSCC are age 65 years or older; however, much of the evidence base informing treatment decisions is based on substantially younger and healthier clinical trial populations. The purpose of this study was to assess the patterns of care of older HNSCC patients to better understand how age is associated with treatment decisions.MethodsUsing the Surveillance, Epidemiology, and End Results (SEER)-Medicare database (1992–2007), we identified patients with non-metastatic HNSCC (n = 10,867) and categorized them by treatment: surgery vs. non-surgery and chemoradiotherapy (CRT) vs. radiotherapy (RT). Multivariate logistic regression models were used to identify variables associated with the receipt of surgery and CRT.ResultsIncreasing age was associated with decreased odds of receiving CRT (OR = 0.94; 95% CI 0.93–0.94) but not surgery (OR 1.00; 95% CI 0.99–1.00). Co-morbidity and race were not associated with receipt of either surgery or CRT. Utilization of CRT increased while surgery decreased between 1992 and 2007.ConclusionAge may influence the receipt of CRT for older HNSCC patients. There has been an increasing trend in the receipt of CRT and a decrease in primary surgery.     

Adjuvant bevacizumab for melanoma patients at high risk of recurrence: survival analysis of the AVAST-M trial

BackgroundBevacizumab is a recombinant humanised monoclonal antibody to vascular endothelial growth factor shown to improve survival in advanced solid cancers. We evaluated the role of adjuvant bevacizumab in melanoma patients at high risk of recurrence.Patients and methodsPatients with resected AJCC stage IIB, IIC and III cutaneous melanoma were randomised to receive either adjuvant bevacizumab (7.5 mg/kg i.v. 3 weekly for 1 year) or standard observation. The primary end point was detection of an 8% difference in 5-year overall survival (OS) rate; secondary end points included disease-free interval (DFI) and distant metastasis-free interval (DMFI). Tumour and blood were analysed for prognostic and predictive markers.ResultsPatients (n=1343) recruited between 2007 and 2012 were predominantly stage III (73%), with median age 56 years (range 18–88 years). With 6.4-year median follow-up, 515 (38%) patients had died [254 (38%) bevacizumab; 261 (39%) observation]; 707 (53%) patients had disease recurrence [336 (50%) bevacizumab, 371 (55%) observation]. OS at 5 years was 64% for both groups [hazard ratio (HR) 0.98; 95% confidence interval (CI) 0.82–1.16, P = 0.78). At 5 years, 51% were disease free on bevacizumab versus 45% on observation (HR 0.85; 95% CI 0.74–0.99, P = 0.03), 58% were distant metastasis free on bevacizumab versus 54% on observation (HR 0.91; 95% CI 0.78–1.07, P = 0.25). Forty four percent of 682 melanomas assessed had a BRAF^V600 mutation. In the observation arm, BRAF mutant patients had a trend towards poorer OS compared with BRAF wild-type patients (P = 0.06). BRAF mutation positivity trended towards better OS with bevacizumab (P = 0.21).ConclusionsAdjuvant bevacizumab after resection of high-risk melanoma improves DFI, but not OS. BRAF mutation status may predict for poorer OS untreated and potential benefit from bevacizumab.Clinical Trial InformationISRCTN 81261306; EudraCT Number: 2006-005505-64