Postoperative radiotherapy versus no postoperative radiotherapy in patients with completely resected non-small-cell lung cancer and proven mediastinal N2 involvement (Lung ART): an open-label, randomised, phase 3 trial.

BACKGROUND: In patients with non-small-cell lung cancer (NSCLC), the use of postoperative radiotherapy (PORT) has been controversial since 1998, because of one meta-analysis showing a deleterious effect on survival in patients with pN0 and pN1, but with an unclear effect in patients with pN2 NSCLC. Because many changes have occurred in the management of patients with NSCLC, the role of three-dimensional (3D) conformal PORT warrants further investigation in patients with stage IIIAN2 NSCLC. The aim of this study was to establish whether PORT should be part of their standard treatment. METHODS: Lung ART is an open-label, randomised, phase 3, superiority trial comparing mediastinal PORT to no PORT in patients with NSCLC with complete resection, nodal exploration, and cytologically or histologically proven N2 involvement. Previous neoadjuvant or adjuvant chemotherapy was allowed. Patients aged 18 years or older, with an WHO performance status of 0-2, were recruited from 64 hospitals and cancer centres in five countries (France, UK, Germany, Switzerland, and Belgium). Patients were randomly assigned (1:1) to either the PORT or no PORT (control) groups via a web randomisation system, and minimisation factors were the institution, administration of chemotherapy, number of mediastinal lymph node stations involved, histology, and use of pre-treatment PET scan. Patients received PORT at a dose of 54 Gy in 27 or 30 daily fractions, on five consecutive days a week. Three dimensional conformal radiotherapy was mandatory, and intensity-modulated radiotherapy was permitted in centres with expertise. The primary endpoint was disease-free survival, analysed by intention to treat at 3 years; patients from the PORT group who did not receive radiotherapy and patients from the control group with no follow-up were excluded from the safety analyses. This trial is now closed. This trial is registered with ClinicalTrials.gov number, NCT00410683. FINDINGS: Between Aug 7, 2007, and July 17, 2018, 501 patients, predominantly staged with 18F-fluorodeoxyglucose (18F-FDG) PET (456 [91%]; 232 (92%) in the PORT group and 224 (90%) in the control group), were enrolled and randomly assigned to receive PORT (252 patients) or no PORT (249 patients). At the cutoff date of May 31, 2019, median follow-up was 4·8 years (IQR 2·9-7·0). 3-year disease-free survival was 47% (95% CI 40-54) with PORT versus 44% (37-51) without PORT, and the median disease-free survival was 30·5 months (95% CI 24-49) in the PORT group and 22·8 months (17-37) in the control group (hazard ratio 0·86; 95% CI 0·68-1·08; p=0·18). The most common grade 3-4 adverse events were pneumonitis (13 [5%] of 241 patients in the PORT group vs one [<1%] of 246 in the control group), lymphopenia (nine [4%] vs 0), and fatigue (six [3%] vs one [<1%]). Late-grade 3-4 cardiopulmonary toxicity was reported in 26 patients (11%) in the PORT group versus 12 (5%) in the control group. Two patients died from pneumonitis, partly related to radiotherapy and infection, and one patient died due to chemotherapy toxicity (sepsis) that was deemed to be treatment-related, all of whom were in the PORT group. INTERPRETATION: Lung ART evaluated 3D conformal PORT after complete resection in patients who predominantly had been staged using (18F-FDG PET-CT and received neoadjuvant or adjuvant chemotherapy. 3-year disease-free survival was higher than expected in both groups, but PORT was not associated with an increased disease-free survival compared with no PORT. Conformal PORT cannot be recommended as the standard of care in patients with stage IIIAN2 NSCLC. FUNDING: French National Cancer Institute, Programme Hospitalier de Recherche Clinique from the French Health Ministry, Gustave Roussy, Cancer Research UK, Swiss State Secretary for Education, Research, and Innovation, Swiss Cancer Research Foundation, Swiss Cancer League.

Neoadjuvant chemotherapy alters the balance of effector to suppressor immune cells in advanced ovarian cancer.

BACKGROUND: At diagnosis, tumor-infiltrating lymphocytes (TILs) are prognostic in epithelial ovarian cancer (EOC). We recently demonstrated that neoadjuvant chemotherapy (NACT) significantly increased stromal TILs. Here, we investigated the impact of NACT on immune subpopulations with a particular focus on the balance of immune-reactive to tolerant subpopulations. MATERIALS AND METHODS: Tissue microarrays of EOC (145 pre-NACT, 139 post-NACT) were analyzed for CD3+, CD8+, FOXP3+, CD68+, and CD163+ by immunohistochemistry and CD4+ cells from deduction. Stromal TILs scored as percentage of stromal area, while intra-epithelial TILs scored as number of TILs in contact with tumor cells/HPF. Differences were evaluated by Wilcoxon or Chi square tests, Wilcoxon signed-rank for paired analyses, and cox model for PFS and OS. RESULTS: NACT significantly increased stromal CD3+ (p = 0.003) and CD8+ (p = 0.001) and intra-epithelial CD8+ (p = 0.022) and CD68+ (p = 0.0003) infiltration in unmatched samples and among paired samples for stromal CD3+ and CD8+. Neither CD3+, CD8+, CD4+, and CD68+ nor CD163+ expression correlated with outcome at diagnosis or post NACT. Using median value as a cut-off, high stromal CD8+/FOXP3+ ratio (HR = 0.59; p = 0.017) and high stromal CD3+/FOXP3+ ratio post NACT were associated with prolonged PFS (p = 0.0226). The more the balance shifted in favor of effector versus regulatory TILs, the better the survival. Similarly, high CD68+/CD163+ ratio post NACT improved PFS (p = 0.0445). CONCLUSION: NACT has a significant impact on the balance of immune-reactive to immune-tolerant subpopulations and a high ratio of CD8+/FOXP3+, CD3+/FOXP3+, and CD68+/CD163+ post NACT was significantly associated with improved outcomes. Whether this could select patients for immunotherapy in the post-operative setting should be investigated.

Impact of young age on platinum response in women with epithelial ovarian cancer: Results of a large single-institution registry.

OBJECTIVE: In young women, EOC is a rare disease with an uncertain genetic and biological substrate. METHODS: We report a long follow-up of EOC patients treated at Gustave Roussy between 1990 and 2009. We matched young patients aged ≤30 years to randomly selected older patients aged ≥40 years according to known prognostic factors (i.e. FIGO stage, histology and surgical residual disease) and the date of diagnosis with a threshold at the year 2000 to balance the treatment procedures. RESULTS: EOC was diagnosed in 68 patients aged ≤30 years matched with 111 patients aged ≥40 years. Low-grade (LG) (i.e. serous and endometrioid) (52%, n = 35) and mucinous (i.e. 23%, n = 16 infiltrative and 12% n = 8 expansile) tumors are prevalent. High-grade (HG) tumors are rare (7%, n = 5). Early stage diseases (53%, n = 36 FIGO I/II) are predominant. Response to platinum based chemotherapy is observed to be inferior in young patients as compared to matched older patients (ORR, 29 vs 84% p = 0.0002). For HG tumors the PFS is of 0% at 5 and 10 years in younger as compared to 30% in older patients. No difference in PFS (median 4.9 vs 9.8 ms, p = 0.58) and OS (not reached vs 15.3 ms, p = 0.47) is found overall among younger and older patients respectively. The median follow-up was 72 months (range, 11-288 months). No genetic abnormalities were found. CONCLUSIONS: Young EOC patients are most often diagnosed at an early FIGO stage with LG serous or mucinous histology. Tumors are significantly more resistant to platinum-based chemotherapy in younger patients.

Cost-effectiveness of preoperative magnetic resonance imaging to optimize surgery in ductal carcinoma in situ of the breast.

PURPOSE: Complete surgical excision is the main factor for successful breast-conserving surgery in patients with ductal carcinoma in situ (DCIS) of the breast. Preoperative magnetic resonance imaging (MRI) may allow surgery optimization in this indication. From an economic standpoint, systematic preoperative MRI is associated with an extra cost, which may be offset by a decrease in the number of re-interventions. We performed an economic evaluation alongside IRCIS randomised controlled trial (NCT01112254) to determine whether systematic preoperative MRI in DCIS is a cost-effective strategy. METHODS: 360 patients were included in IRCIS trial. Costs were assessed from the French national health insurance perspective. Resource use was prospectively collected during a 6-month period after randomisation. We estimated the mean cost per averted re-intervention. RESULTS: Despite extra costs due to MRI and additional biopsies, difference in total costs between arms was not statistically significant (mean cost of €9980 in MRI arm and €9682 in no MRI arm, cost difference: €298 [CI95% : -470; 1063]). There was a non-significant decrease in the rate of re-hospitalisations for positive or close margins (20% in MRI arm versus 27% in No MRI arm, difference -7% [CI95% : -17; 3]). At a willingness to pay of €500 to avert a re-intervention, the probability that MRI strategy is cost-effective was 93%. CONCLUSION: Systematic preoperative MRI in patients with DCIS of the breast may be a cost-effective strategy. However, the modest clinical benefit associated with such a strategy limits the interest for this procedure in routine practice given the current MRI techniques.

Clinical utility of SMARCA4 testing by immunohistochemistry in rare ovarian tumours.

BACKGROUND: Ovarian small cell carcinoma, hypercalcaemic type (SCCOHT) is a rare and lethal disease affecting young women. As histological diagnosis is challenging and urgent, there is a clear need for a robust diagnostic test. While mutations in the chromatin-remodelling gene, SMARCA4, appear to be typical, it may not be feasible routinely to be clinically relevant. METHODS: Previous studies have described the value of SMARCA4 IHC to differentiate SCCOHT from ovarian neoplasms (ON), with similar histologic appearances. We aimed to evaluate its clinical utility among a cohort of 44 SCCOHT and 94 rare ON frequently misdiagnosed as SCCOHT. RESULTS: Forty-three percent (16/36) of SCCOHT had been classified locally as non-SCCOHT confirming the diagnosis challenge. Sensitivity and specificity of SMARCA4 IHC were excellent at 88% and 94%, respectively. In a community setting with a much lower prevalence of the disease, estimated PPV is 40% while NPV remained high at 99%. Finally, among the 16 SCCOHT misclassified locally, SMARCA4 IHC testing would have resulted in corrected diagnosis in 88% of cases. CONCLUSIONS: SMARCA4 IHC is a highly sensitive, and specific test for the diagnosis of SCCOHT and is of huge clinical utility in providing a timely and accurate diagnosis of this challenging disease.

Increased bone marrow SUVmax on 18F-FDG PET is associated with higher pelvic treatment failure in patients with cervical cancer treated by chemoradiotherapy and brachytherapy.

The aim of this study was to evaluate if bone marrow (BM) SUVmax measured on pre-treatment 18F-FDG PET/CT predicts the clinical outcome of locally advanced cervical cancer (LACC). We recruited retrospectively patients with LACC who underwent staging 18F-FDG PET/CT and had baseline blood tests, then treated by chemoradiation therapy (CRT), followed by image-guided adaptive brachytherapy (IGABT). BM SUVmax was calculated and correlated to inflammatory blood markers. Tumor size and pelvic lymph node involvement were evaluated on baseline MRI. Prognostic value of SUV uptake and blood markers regarding overall survival (OS), pelvic and extra-pelvic recurrence-free survival (PRFS and EPRFS respectively) was assessed using Cox models with adjusted p-values. 116 patients with FIGO stage Ib-IVa cervical cancer, treated between 2005 and 2014, were analyzed. The median follow-up was 75.5 months. BM SUVmax was significantly correlated to tumor SUVmax. In multivariate analysis, PRFS was significantly poorer in patients with high BM SUVmax (>2.8) and neutrophilia (p < .05). Tumor size (>5 vs ≤5 cm) could predict PRFS, EPRFS and OS (p < .05). In our cohort, FIGO stage (I-II vs III-IV), pelvic lymph node involvement and tumor SUVmax (>12 vs ≤12) were not prognostic for OS or pelvic and extra-pelvic relapses. Patients with LACC and high BM SUVmax on 18F-FDG PET have worse PFRS following CRT plus IGABT. These results can be potentially explained by the pro-inflammatory role of the tumor microenvironment and G-CSF expressed by tumor cells. These data support the role of PET as a potential indicator of disease aggressiveness beyond tumor staging.

Preoperative Breast Magnetic Resonance Imaging in Women With Local Ductal Carcinoma in Situ to Optimize Surgical Outcomes: Results From the Randomized Phase III Trial IRCIS.

PURPOSE: We evaluated the addition of breast magnetic resonance imaging (MRI) to standard radiologic evaluation on the re-intervention rate in women with ductal carcinoma in situ (DCIS) undergoing breast-conserving surgery. PATIENTS AND METHODS: Women with biopsy-proven DCIS corresponding to a unifocal microcalcification cluster or a mass less than 30 mm were randomly assigned to undergo MRI or standard evaluation. The primary end point was the re-intervention rate for positive or close margins (< 2 mm) in the 6 months after randomization ( ClinicalTrials.gov identifier: NCT01112254). RESULTS: A total of 360 patients from 10 hospitals in France were included in the study. Of the 352 analyzable patients, 178 were randomly assigned to the MRI arm, and 174 were assigned to the control arm. In the intent-to-treat analysis, 82 of 345 patients with the assessable end point were reoperated for positive or close margins within 6 months, resulting in a re-intervention rate of 20% (35 of 173) in the MRI arm and 27% (47 of 172) in the control arm. The absolute difference of 7% (95% CI, -2% to 16%) corresponded to a relative reduction of 26% (stratified odds ratio, 0.68; 95% CI, 0.41 to 1.1; P = .13). When considering only the per-protocol population with an assessable end point, the difference was 9% (stratified odds ratio, 0.59; 95% CI, 0.35 to 1.0; P = .05). Total mastectomy rates were 18% (31 of 176) in the MRI arm and 17% (30 of 173) in the control arm (stratified P = .93). For 100 lesions seen on MRI, nonmass-like enhancement was more predominant (82%) than mass enhancement (20%). Nevertheless, no specific morphologic and kinetic parameters for DCIS were identified. CONCLUSION: The study did not show sufficient surgical improvement with the use of preoperative MRI to be clinically relevant in DCIS staging. However, this could be reconsidered with the improvement of new MRI sequences and new modalities in magnetic resonance techniques.

Clinical Response to Induction Chemotherapy Predicts Outcome after Combined-Modality Therapy in Inflammatory Breast Cancer.

PURPOSE: To assess predictors of outcome in a cohort of Inflammatory Breast Cancer (IBC) patients receiving induction chemotherapy followed by local treatment. METHODS: We retrospectively reviewed 95 non-metastatic IBC patient files. RESULTS: Complete clinical response (cCR) was obtained in 15 (16%) patients. Median follow up was 13.4 years (IC95%: 10.4-14.6). Loco-regional control (LC), disease-free survival (DFS), and overall survival (OS) at 5 years were 85%, 41%, and 55%, respectively; cCR was associated with better DFS and OS in multivariate analyses adjusted for age (p = 0.02). CONCLUSIONS: Clinical response to upfront chemotherapy predicts the outcome of patients affected by IBC.

LACE-Bio: Validation of Predictive and/or Prognostic Immunohistochemistry/Histochemistry-based Biomarkers in Resected Non-small-cell Lung Cancer.

BACKGROUND: Complete resection of non-small-cell lung cancer (NSCLC) offers the potential for cure after surgery and adjuvant chemotherapy. Patients may not benefit and may experience severe toxicity. There are no validated molecular tools to allow better patient selection. MATERIALS AND METHODS: The LACE-Bio (LACE [Lung Adjuvant Cisplatin Evaluation]) project includes 4 trials (International Adjuvant Lung Cancer Trial [IALT], Adjuvant Navelbine International Trialist Association [ANITA], JBR10, and Cancer and Leukemia Group B (CALGB)-9633). Immunohistochemistry biomarkers shown in one trial to have a prognostic/predictive effect on overall survival were tested. RESULTS: The majority of the promising biomarkers could not be validated; the prognostic effect of tumor infiltrating lymphocytes and ß-tubulin was confirmed. Potential causes include tissue fixation, storage, the use of tissue microarrays, and varying reagent/antibody batches. CONCLUSIONS: Immunohistochemistry assays from single trials may be misleading and require validation before being used for patient selection. LACE-Bio-2 is evaluating potential genomic biomarkers that may allow more precise selection of patients with NSCLC for adjuvant chemotherapy in NSCLC.

Patient-assisted compression helps for image quality reduction dose and improves patient experience in mammography.

We evaluated the impact of patient-assisted compression (PAC) on image quality, dose, workflow and patient experience of mammography. Patients aged 40-90 years coming for bilateral mammography were included prospectively in the study. After positioning each breast, the technologist performed the compression and exposure of the first breast, initiated the compression of the other until 3 daN and then let the patient complete the compression using a remote control device. Image quality, compression force, breast thickness, average glandular dose and pain value for each breast were assessed for PAC and technologist compression (TC). The compression level was significantly higher with PAC than TC for both craniocaudal (CC; median difference 2.0 daN, p < 0.0001) and mediolateral oblique (MLO) views (median difference 1.5 daN, p < 0.0001). Breast thickness was reduced with PAC (CC, median difference -1.90 cm, p = 0.02), as well as glandular dose (CC, median difference -0.03, p = 0.02). The image quality was rated equivalent for both modes in 85% (85/100) of cases, superior for PAC in 10% (10/100) of cases and inferior in 5% (5/100) of cases. There was no significant difference in discomfort or pain felt between PAC and TC modes. Seventy-four percent of patients reported that the self-compressing device would facilitate their reattendance. PAC may be a suitable technique for mammography examinations, providing an equivalent image quality to TC. Moreover, as the breast compression level is increased, PAC may help reduce breast thickness, hence glandular dose. The fact that patients have control over the procedure may change their perception of mammography and improve uptake and compliance.

Breast tissue density change after oophorectomy in BRCA mutation carrier patients using visual and volumetric analysis.

OBJECTIVE: BRCA1/2 mutations account for 30-50% of hereditary breast cancers and bilateral oophorectomy is associated with a reduced risk of breast cancer in these patients. Breast density is a well-established breast cancer risk factor and is also associated with increased risk in BRCA carriers. The aim of the study was to evaluate the impact of oophorectomy on mammographic breast density and to assess which method of breast density assessment is more sensitive to change over time. METHODS: Retrospective study of 50 BRCA1/2 patients who underwent bilateral oophorectomy and had at least a baseline and post-surgery mammogram. Mammographic breast density was determined by Volpara and consensus visual assessment by two radiologists. The primary endpoint was change in density between baseline and the first mammogram post-surgery. RESULTS: At baseline, there was a non-significant trend for decreased density with increasing age. Volumetric breast density (VBD) significantly decreased after oophorectomy from a median VBD of 12.5% at baseline to 10.2% post-surgery which was driven by a reduction in fibroglandular volume. There was a higher absolute decrease in VBD in patients aged between 40-50 (p < 0.01). Using Volpara Density Grades (analogous to BI-RADS 4th edition density categories), 84% of females displayed a decrease in density category over the study period compared to only 76% using the radiologists' visual classification (p < 0.001) Conclusion: Oophorectomy is associated with a decrease in breast density and younger patients exhibit a larger absolute decrease. Volpara is more sensitive to identify change over time compared to visual assessment. Advances in knowledge: Oophorectomy is associated with a significant decrease in VBD in patients with BRCA mutations and Volpara Density Grades were more sensitive to identify decreases in density compared to visually assessed BI-RADS categories. Decreases in breast density following oophorectomy surgery in BRCA patients may be one of the mechanisms contributing to the observed decreased breast cancer risk after surgery. However, further studies are needed to investigate the relationship between breast density, oophorectomy and breast cancer risk in BRCA patients.

Value of whole breast magnetic resonance elastography added to MRI for lesion characterization.

The purpose of this work was to assess the diagnostic value of magnetic resonance elastography (MRE) in addition to MRI to differentiate malignant from benign breast tumors, and the feasibility of performing MRE on the whole breast. MRE quantified biomechanical properties within the entire breast (50 slices) using an 11 min acquisition protocol at an isotropic image acquisition resolution of 2 × 2 × 2 mm3 . Fifty patients were included. Finally, 43 patients (median age 52) with a suspect breast lesion detected by mammography and/or ultrasound were examined by MRI and MRE at 1.5 T. The viscoelastic parameters, i.e. elasticity (Gd ), viscosity (Gl ), the magnitude of the complex shear modulus Gd2+Gl2, and the phase angle y=2πatanGlGd, were measured via MRE and correlated with MRI Breast Imaging-Reporting and Data System (BI-RADS) score, histological type, and histological grade. Stroma component and angiogenesis were also correlated with viscoelastic properties. In the 43 lesions, Gd decreased and y increased with the MRI BI-RADS score (pGd  = 0.02, py  = 0.002), whereas (Gl ) and y were increased in malignant lesions (pGl  = 0.045, py  = 0.0004). The area under the curve increased from 0.84 for MRI BI-RADS alone to 0.92 with the MRI BI-RADS and y (AUC increase +0.08; 95% CI (-0.003; 0.16)). Lesion characterization using the y parameter increased the diagnostic accuracy. The phase angle y was found to have a significant role (p = 0.01) in predicting malignancy independently of the MRI BI-RADS. Interestingly, histological analysis showed no correlation between viscoelastic parameters and percentage and type of stroma, CD34 quantification of vessels, or histological grade. The combination of MRE and MRI improves the diagnostic accuracy for breast lesions in the studied cohort. In particular, the phase angle y was found to have a significant role in predicting malignancy in addition to BI-RADS.

Interleukin-15 Is Associated with Severity and Mortality in Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis.

Early diagnosis and prognosis monitoring for Stevens-Johnson syndrome/toxic epidermal necrolysis (TEN) still remain a challenge. This study aims to explore any cytokine/chemokine with prognostic potential in Stevens-Johnson syndrome/TEN. Through screening a panel of 28 serological factors, IL-6, IL-8, IL-15, tumor necrosis factor-α, and granulysin were upregulated in patients with Stevens-Johnson syndrome/TEN and selected for the further validation in total 155 patients with Stevens-Johnson syndrome/TEN, including 77 from Taiwan and 78 from the Registry of Severe Cutaneous Adverse Reactions. Among these factors evaluated, the levels of IL-15 (r = 0.401; P < 0.001) and granulysin (r = 0.223; P = 0.026) were significantly correlated with the disease severity in 112 samples after excluding patients with insufficient data to calculate the score of TEN. In addition, IL-15 was also associated with mortality (P = 0.002; odds ratio, 1.09; 95% confidence interval, 1.03-1.14; P = 0.001; adjusted odds ratio, 1.10; 95% confidence interval, 1.04-1.16). Consistent results were obtained after the exclusion of Taiwanese patients with sepsis to rule out possible confounders. Moreover, IL-15 was shown to enhance cytotoxicity of cultured natural killer cells and blister cells from patients with TEN. Our findings highlight a usefulness of IL-15 in prognosis monitoring and therapeutic intervention of this devastating condition.

Impact of primary para-aortic lymphadenectomy on distant failure in locally advanced cervical cancer patients treated in the era of image-guided adaptive brachytherapy.

To investigate the impact of a primary para-aortic lymphadenectomy (PAL) in locally advanced cervical cancer patients receiving definitive chemoradiation, we reviewed the clinical records of consecutive patients treated in our Institution and receiving an external beam irradiation followed with an image-guided adaptive brachytherapy for a locally advanced cervical cancer. We examined the impact of performing a primary PAL as part of primary staging for guiding irradiation fields in patients without extra-pelvic PET uptake. The outcome of patients presenting para-aortic lymph node uptake (PALNU) was also examined. 186 patients were identified. Median follow-up was 44.4 months. Patients receiving a primary PAL (PAL group) and those who received upfront pelvic chemoradiation (no-PAL group) did not significantly differ for loco-regional failures. Survival without distant failure (DFFS), including para-aortic relapses, was at 3 years 87 % (95 % CI 84-90 %) in PAL group, 67 % (95 % CI 59-85 %) in the no-PAL group and 44 % (95 % CI 32-66 %) in the PALNU group (p = 0.04 for comparison between PAL and no-PAL groups). In a multivariate model including para-aortic lymphadenectomy, pelvic nodal uptake and high-risk clinical target volume as adjustment variables, a para-aortic lymphadenectomy was significant for DFS (HR = 0.47, 95 % CI 0.26-0.84, p = 0.01). Although confounding factors could account for these retrospective results, a primary PAL with tailored irradiation fields based on para-aortic histological findings seems to be associated with a better control for distant metastases. A randomized trial is testing the benefit of this strategy.

European cost-effectiveness study of uPA/PAI-1 biomarkers to guide adjuvant chemotherapy decisions in breast cancer.

BACKGROUND: This study investigated the cost effectiveness of guideline-recommended (American Society of Clinical Oncology, European Society of Medical Oncology) urokinase plasminogen activator (uPA)/plasminogen activator inhibitor-1 (PAI-1) biomarkers to guide adjuvant chemotherapy decisions for hormone receptor-positive, node-negative early breast cancer patients at intermediate risk of relapse, in France, Germany, and The Netherlands. METHODS: uPA/PAI-1 testing was compared to chemotherapy for all patients and to no chemotherapy in two age-related subgroups (35-49 and 50-75 years). A partitioned survival analysis was performed using patient-level data for survival outcomes and secondary sources. Mean quality-adjusted life years (QALYs) and costs were estimated over a lifetime horizon to calculate the incremental net monetary benefit (INMB) at a willingness-to-pay of €50,000/QALY. Uncertainty was explored through bootstrap and probabilistic sensitivity analysis using 5000 replicates. RESULTS: In the 35-49 year age group, INMBs were negative when uPA/PAI-1 testing was compared to chemotherapy for all patients but positive when it was compared to no chemotherapy for the three countries. In the 50-75 year age group, INMBs of uPA/PAI-1 testing compared to both reference strategies were positive in the three countries, with cost-effectiveness probabilities for the uPA/PAI-1 strategy of 65%, 70%, and 59% for France, Germany, and the Netherlands, respectively, compared with chemotherapy for all patients, and 64%, 58%, and 65%, respectively, compared with no chemotherapy. CONCLUSIONS: uPA/PAI-1 testing could allow the selection of patients older than 50 years requiring chemotherapy in this population, but the cost effectiveness of this strategy is uncertain. Chemotherapy for all patients is the most cost-effective strategy for patients younger than 50 years.

Added Value of Contrast-Enhanced Spectral Mammography in Postscreening Assessment.

To assess the value on diagnostic and treatment management of contrast-enhanced spectral mammography (CESM), as adjunct to mammography (MG) and ultrasound (US) in postscreening in a breast cancer unit for patients with newly diagnosed breast cancer or with suspicious findings on conventional imaging. Retrospective review of routine use of bilateral CESM performed between September 2012 and September 2013 in 195 women with suspicious or undetermined findings on MG and/or US. CESM images were blindly reviewed by two radiologists for BI-RADS(®) assessment and probability of malignancy. Each lesion was definitely confirmed either with histopathology or follow-up. Two hundred and ninety-nine lesions were detected (221 malignant). CESM sensitivity, specificity, positive-predictive value and negative-predictive value were 94% (CI: 89-96%), 74% (CI: 63-83%), 91% (CI: 86-94%) and 81% (CI: 70-89%), respectively, with 18 false positive and 14 false negative. CESM changed diagnostic and treatment strategy in 41 (21%) patients either after detection of additional malignant lesions in 38 patients (19%)-with a more extensive surgery (n = 21) or neo-adjuvant chemotherapy (n = 1)-or avoiding further biopsy for 20 patients with negative CESM. CESM can be performed easily in a clinical assessment after positive breast cancer screening and may change significantly the diagnostic and treatment strategy through breast cancer staging.

Prognostic Effect of Tumor Lymphocytic Infiltration in Resectable Non-Small-Cell Lung Cancer.

PURPOSE: Tumor lymphocytic infiltration (TLI) has differing prognostic value among various cancers. The objective of this study was to assess the effect of TLI in lung cancer. PATIENTS AND METHODS: A discovery set (one trial, n = 824) and a validation set (three trials, n = 984) that evaluated the benefit of platinum-based adjuvant chemotherapy in non-small-cell lung cancer were used as part of the LACE-Bio (Lung Adjuvant Cisplatin Evaluation Biomarker) study. TLI was defined as intense versus nonintense. The main end point was overall survival (OS); secondary end points were disease-free survival (DFS) and specific DFS (SDFS). Hazard ratios (HRs) and 95% CIs associated with TLI were estimated through a multivariable Cox model in both sets. TLI-histology and TLI-treatment interactions were explored in the combined set. RESULTS: Discovery and validation sets with complete data included 783 (409 deaths) and 763 (344 deaths) patients, respectively. Median follow-up was 4.8 and 6 years, respectively. TLI was intense in 11% of patients in the discovery set compared with 6% in the validation set (P < .001). The prognostic value of TLI in the discovery set (OS: HR, 0.56; 95% CI, 0.38 to 0.81; P = .002; DFS: HR, 0.59; 95% CI, 0.42 to 0.83; P = .002; SDFS: HR, 0.56; 95% CI, 0.38 to 0.82; P = .003) was confirmed in the validation set (OS: HR, 0.45; 95% CI, 0.23 to 0.85; P = .01; DFS: HR, 0.44; 95% CI, 0.24 to 0.78; P = .005; SDFS: HR, 0.42; 95% CI, 0.22 to 0.80; P = .008) with no heterogeneity across trials (P ≥ .38 for all end points). No significant predictive effect was observed for TLI (P ≥ .78 for all end points). CONCLUSION: Intense lymphocytic infiltration, found in a minority of tumors, was validated as a favorable prognostic marker for survival in resected non-small-cell lung cancer.