Evaluation of two modalities of perioperative treatment in the management of extremity and truncal soft tissue sarcomas: neoadjuvant concurrent chemoradiotherapy and sequential treatment.

PURPOSE: Patients with locally advanced grade 2-3 extremity/truncal soft tissue sarcomas (STS) are at high risk of recurrence. The objective of this study was to assess the efficacy and feasibility of neoadjuvant concurrent chemoradiotherapy (cCRT) in selected grade 2-3 patients with limb or trunk wall STS, and to compare this schedule to a sequential approach combining neoadjuvant chemotherapy and adjuvant radiotherapy. METHODS: We retrospectively included patients who underwent neoadjuvant cCRT at two comprehensive cancer centers from 1992-2016. We then compared these results to those of patients treated with preoperative chemotherapy and postoperative radiotherapy from a third comprehensive cancer center with a propensity score matched analysis. RESULTS: A total of 53 patients were treated by neoadjuvant cCRT; 58 patients could be matched with 29 patients in each treatment group after propensity score matching. Disease-free survival and overall survival at 5 years were 54.9 and 63.5%, respectively with neoadjuvant cCRT, with no significant difference when compared to the sequential treatment group. R0 resection rate was higher (90.9 vs 44.8%, p < 0.01) in the cCRT group than in the sequential treatment group during a shorter therapeutic sequence (118 vs 210.5 days, p < 0.01), with no impact on the surgical procedure or postoperative complications. CONCLUSION: cCRT is feasible with acceptable immediate and late toxicities. It could facilitate surgery by increasing the R0 resection rate and improve patient compliance by shortening the therapeutic sequence.

The importance of jointly analyzing treatment administration and toxicity associated with targeted therapies: a case study of regorafenib in soft tissue sarcoma patients.

Background: Different methods have been proposed to analyze adverse events (AEs) associated with targeted therapies. While these AEs lead to dose adjustments for many patients, conventional reporting methods do not take drug administration into consideration. This paper underlines the importance of jointly reporting AEs and drug administration using prevalence, and proposes a complementary approach to reporting. Patients and methods: The prevalence method estimates the probability of progression-free patients being in a particular health state (state 1: AEs with full dose; state 2: AEs with reduced dose; state 3: no AEs with reduced dose) at different time points. To take into account the impact of dose adjustments on efficacy, the weighted prevalence method can be used by assigning utility weights to the different health states. The benefit of these methods was illustrated using data from a phase II trial of regorafenib. Results: Only 4.6% of progression-free patients developed mucositis/stomatitis (grade ≥2) at 3 months. The prevalence of patients not experiencing this AE but whose dose was reduced or treatment interrupted was 58.1%. The weighted prevalence of the regorafenib toxicity profile and dose reduction was higher in the control arm. Conclusion: This case study confirms the importance of jointly analyzing AEs and drug administration. The weighted prevalence approach is an average score that incorporates the dimension of drug administration into AE assessment. This can be helpful for regulatory agencies as well as for clinicians to evaluate the benefit-risk ratio of therapies in their treatment choice. Clinical trial: NCT01900743.

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

Background: Prediction 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. Methods: A 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. Results: CINSARC 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). Conclusion: CINSARC 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.

Prospective Assessment of First-Year Quality of Life After Pelvic Exenteration for Gynecologic Malignancy: A French Multicentric Study.

BACKGROUND: Pelvic exenteration remains one of the most mutilating procedures, with important postoperative morbidity, an altered body image, and long-term physical and psychosocial concerns. This study aimed to assess quality of life (QOL) during the first year after pelvic exenteration for gynecologic malignancy performed with curative intent. METHODS: A French multicentric prospective study was performed by including patients who underwent pelvic exenteration. Quality of life by measurement of functional and symptom scales was assessed using the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 (version 3.0) and the EORTC QLQ-OV28 questionnaires before surgery, at baseline, and 1, 3, 6, and 12 months after the procedure. RESULTS: The study enrolled 97 patients. Quality of life including physical, personal, fatigue, and anorexia reported in the QLQ-C30 was significantly reduced 1 month postoperatively and improved at least to baseline level 1 year after the procedure. Body image also was significantly reduced 1 month postoperatively. Global health, emotional, dyspnea, and anorexia items were significantly improved 1 year after surgery compared with baseline values. Unlike younger patients, elderly patients did not regain physical and social activities after pelvic exenteration. CONCLUSIONS: Therapeutic decision on performing a pelvic exenteration can have a severe and permanent impact on all aspects of patients' QOL. Deterioration of QOL was most significant during the first 3 months after surgery. Elderly patients were the only group of patients with permanent decreased physical and social function. Preoperative evaluation and postoperative follow-up evaluation should include health-related QOL instruments, counseling by a multidisciplinary team to cover all aspects concerning stoma care, sexual function, and long-term concerns after surgery.

Statistical controversies in clinical research: should schedules of tumor size assessments be changed?

BACKGROUND: Time to progression (TTP) is often used as a primary end point in phase II clinical trials. Since the actual date of nadir and progression is never known, most calculated TTP are overestimated. This study evaluates the imprecision on the estimate of TTP under two hypothetical tumor kinetic settings and various assessment schedules. DESIGN: A two-component tumor growth model was used to account for treatment effect assuming exponential decay for tumor shrinkage and linear growth for progression. Evolution of tumor burden (TB) was modelized according to two scenarios using either a cytotoxic or a cytostatic agent and several assessment schedules. TB, nadir, progression and TTP were simulated for each visit schedule. RESULTS: For cytotoxic agents, our model predicted response at 1.5 weeks, a TB at nadir of 40.2 mm (starting from 100 mm) occurring at 6.7 weeks and true progression at 11.2 weeks with a TB of 48.2 mm. For cytostatic agents, our model predicted no response, a TB at nadir of 77 mm occurring at 9.2 weeks and true progression at 19.4 weeks with a TB of 92 mm. Depending on the assessment schedule, estimated TTP was increased from 0.8 to 36.8 weeks and from 0.6 to 28.6 weeks when compared with the true TTP and varied from 5.2% to 298% and from 1.66 to 109.58% when compared with the true TB at progression for cytotoxic and cytostatic agents, respectively. Our model further shows that for cytotoxic agents, evaluation of TB every 6 weeks is optimal to capture the true nadir, the time to nadir, the true progression and the true TTP, whereas for cytostatic agents, this evaluation is optimal every 10 weeks. CONCLUSIONS: Our results emphasize the importance to estimate the effects of tested drugs on tumor shrinkage before design any phase II clinical trials to choose optimal TB evaluation's timing.

How to report toxicity associated with targeted therapies?

BACKGROUND: In the era of personalized medicine, molecularly targeted therapies (MTT) have modified the outcome of some cancer types. The price of tumor control needs to be balanced with toxicity since these new therapies are administered continuously for several months or sometimes for several years. For cytotoxic drugs, the incidence of adverse event (AE) was traditionally reported as frequency and intensity. This simple measure is not sufficient to capture the recurrent nature and duration of AE. This paper presents two methods to better describe the toxicity burden across the time: prevalence and Q-TWiST. PATIENTS AND METHODS: Limitation of worst-grade method and advantages of prevalence and Q-TWiST in the analysis of toxicity were illustrated using data from a phase II trial and a hypothetically simulated clinical trial. RESULTS: Prevalence integrates the recurrent nature of AE. Using prevalence, it is possible to obtain a time profile of AE. Q-TWiST method evaluates the weighted time spent in each health state and also considers the recurrent nature of side-effects in order to assess the 'risk-benefit' ratio of a treatment. When interpreting Q-TWiST results, it is necessary to take into account overall survival and progression-free survival and to define a clinically relevant difference according to the setting. CONCLUSION: The two methods presented here capture different effects. They are helpful for physicians in their treatment choice (balance benefit risk), to counsel patients and to optimize supportive care. In order to ensure consistency and provide critical information required for medical decision-making, it is important to encourage the use of alternative statistical methods in the analysis of toxicities associated with MTT. CLINICAL TRIAL: NCT00541008.

Lung cancer patients with HER2 mutations treated with chemotherapy and HER2-targeted drugs: results from the European EUHER2 cohort.

BACKGROUND: HER2 mutations have been identified as oncogenic drivers in lung cancers and are found in 1-2% of lung adenocarcinomas. There is, to date, no standard of care for these patients. We thus aim to study the therapeutic outcomes of patients harboring HER2 mutations and establish the efficacy of various drug regimens. PATIENTS AND METHODS: This retrospective cohort study in European centers assessed patients with advanced non-small-cell lung cancer (NSCLC), a known HER2 exon-20 insertion, treated with chemotherapy and/or HER2-targeted drugs. RESULTS: We identified 101 eligible patients from 38 centers: median age 61 years (range: 30-87), 62.4% women, 60.4% never-smokers. All tumors were adenocarcinomas. Concomitant EGFR mutations, ALK translocations, and ROS translocations were observed in 5, 1, and 1 patients, respectively. The median number of treatment lines was 3 (range: 1-11). The median overall survival was 24 months. Overall response rate (ORR) and the median progression-free survival (PFS) with conventional chemotherapy (excluding targeted therapies) were 43.5% and 6 months in first-line (n = 93), and 10% and 4.3 months in second-line (n = 52) therapies. Sixty-five patients received HER2-targeted therapies: trastuzumab = 57, neratinib = 14, afatinib = 9, lapatinib = 5, T-DM1 = 1. ORR was 50.9% and PFS was 4.8 months with trastuzumab or T-DM1. CONCLUSION: This series shows the chemosensitivity of HER2-driven NSCLC, and the potential interest of HER2-targeted agents. Our results should help to define the best therapeutic strategy for these patients and to orient future clinical trials.

Prediction of long-term cumulative incidences based on short-term parametric model for competing risks: application in early breast cancer.

Use of parametric statistical models can be a solution to reduce the follow-up period time required to estimate long-term survival. Mould and Boag were the first to use the lognormal model. Competing risks methodology seems more suitable when a particular event type is of interest than classical survival analysis. The objective was to evaluate the ability of the Jeong and Fine model to predict long-term cumulative incidence. Survival data recorded by Institut Curie (Paris) from 4761 breast cancer patients treated and followed between 1981 and 2013 were used. Long-term cumulative incidence rates predicted by the model using short-term follow-up data were compared to non-parametric estimation using complete follow-up data. 20- or 25-year cumulative incidence rates for loco-regional recurrence and distant metastasis predicted by the model using a maximum of 10 years of follow-up data had a maximum difference of around 6 % compared to non-parametric estimation. Prediction rates were underestimated for the third and composite event (contralateral or second cancer or death). Predictive ability of Jeong and Fine model on breast cancer data was generally good considering the short follow-up period time used for the estimation especially when a proportion of patient did not experience loco-regional recurrence or distant metastasis.

Surgical Complexity Impact on Survival After Complete Cytoreductive Surgery for Advanced Ovarian Cancer.

INTRODUCTION: The direct relationship between surgical radicality to compensate biologic behavior and improvement of patient outcome at the time of primary or interval cytoreduction remains unclear. OBJECTIVE: The aim of this study was to evaluate the impact of disease extension and surgical complexity on survival after complete macroscopic resection for stage IIIC-IV ovarian cancer. MATERIALS AND METHODS: Medical records from seven referral centers in France were reviewed to identify all patients who had complete cytoreductive surgery for stage IIIC-IV epithelial ovarian, fallopian, or primary peritoneal cancer. All patients had at least six cycles of carboplatin and paclitaxel combination therapy. RESULTS: From the 374 consecutive patients with complete cytoreduction who were included in this study, stage, grade, upper abdominal disease, surgical complexity, and carcinomatosis extent were significantly associated with disease-free survival (DFS) at univariate analysis. Stage IV and the need for ultra-radical procedures were significantly associated with lower overall survival (OS). On multivariate analysis, radical surgery, including more than two visceral resections, was significantly associated with decreased DFS and OS. CONCLUSIONS: Patients who need complex surgical procedures involving two or more visceral resections in order to achieve successful complete cytoreduction have worse outcome than patients with less extensive procedures. The negative impact of surgical complexity was not significant in patients who underwent upfront procedures. Tumor volume and extension were associated with decreased DFS in patients undergoing a primary surgical approach. This adds to the evidence that, even though complete cytoreduction is currently the objective of surgery, tumor load remains an independent poor prognostic factor and probably reflects a more aggressive behavior.

Guidelines for time-to-event end point definitions in breast cancer trials: results of the DATECAN initiative (Definition for the Assessment of Time-to-event Endpoints in CANcer trials)†.

BACKGROUND: Using surrogate end points for overall survival, such as disease-free survival, is increasingly common in randomized controlled trials. However, the definitions of several of these time-to-event (TTE) end points are imprecisely which limits interpretation and cross-trial comparisons. The estimation of treatment effects may be directly affected by the definitions of end points. The DATECAN initiative (Definition for the Assessment of Time-to-event Endpoints in CANcer trials) aims to provide recommendations for definitions of TTE end points. We report guidelines for randomized cancer clinical trials (RCTs) in breast cancer. PATIENTS AND METHODS: A literature review was carried out to identify TTE end points (primary or secondary) reported in publications of randomized trials or guidelines. An international multidisciplinary panel of experts proposed recommendations for the definitions of these end points based on a validated consensus method that formalize the degree of agreement among experts. RESULTS: Recommended guidelines for the definitions of TTE end points commonly used in RCTs for breast cancer are provided for non-metastatic and metastatic settings. CONCLUSION: The use of standardized definitions should facilitate comparisons of trial results and improve the quality of trial design and reporting. These guidelines could be of particular interest to those involved in the design, conducting, reporting, or assessment of RCT.

Guidelines for time-to-event end point definitions in sarcomas and gastrointestinal stromal tumors (GIST) trials: results of the DATECAN initiative (Definition for the Assessment of Time-to-event Endpoints in CANcer trials)†.

BACKGROUND: The use of potential surrogate end points for overall survival, such as disease-free survival (DFS) or time-to-treatment failure (TTF) is increasingly common in randomized controlled trials (RCTs) in cancer. However, the definition of time-to-event (TTE) end points is rarely precise and lacks uniformity across trials. End point definition can impact trial results by affecting estimation of treatment effect and statistical power. The DATECAN initiative (Definition for the Assessment of Time-to-event End points in CANcer trials) aims to provide recommendations for definitions of TTE end points. We report guidelines for RCT in sarcomas and gastrointestinal stromal tumors (GIST). METHODS: We first carried out a literature review to identify TTE end points (primary or secondary) reported in publications of RCT. An international multidisciplinary panel of experts proposed recommendations for the definitions of these end points. Recommendations were developed through a validated consensus method formalizing the degree of agreement among experts. RESULTS: Recommended guidelines for the definition of TTE end points commonly used in RCT for sarcomas and GIST are provided for adjuvant and metastatic settings, including DFS, TTF, time to progression and others. CONCLUSION: Use of standardized definitions should facilitate comparison of trials' results, and improve the quality of trial design and reporting. These guidelines could be of particular interest to research scientists involved in the design, conduct, reporting or assessment of RCT such as investigators, statisticians, reviewers, editors or regulatory authorities.

Guidelines for the definition of time-to-event end points in renal cell cancer clinical trials: results of the DATECAN project†.

BACKGROUND: In clinical trials, the use of intermediate time-to-event end points (TEEs) is increasingly common, yet their choice and definitions are not standardized. This limits the usefulness for comparing treatment effects between studies. The aim of the DATECAN Kidney project is to clarify and recommend definitions of TEE in renal cell cancer (RCC) through a formal consensus method for end point definitions. MATERIALS AND METHODS: A formal modified Delphi method was used for establishing consensus. From a 2006-2009 literature review, the Steering Committee (SC) selected 9 TEE and 15 events in the nonmetastatic (NM) and metastatic/advanced (MA) RCC disease settings. Events were scored on the range of 1 (totally disagree to include) to 9 (totally agree to include) in the definition of each end point. Rating Committee (RC) experts were contacted for the scoring rounds. From these results, final recommendations were established for selecting pertinent end points and the associated events. RESULTS: Thirty-four experts scored 121 events for 9 end points. Consensus was reached for 31%, 43% and 85% events during the first, second and third rounds, respectively. The expert recommend the use of three and two endpoints in NM and MA setting, respectively. In the NM setting: disease-free survival (contralateral RCC, appearance of metastases, local or regional recurrence, death from RCC or protocol treatment), metastasis-free survival (appearance of metastases, regional recurrence, death from RCC); and local-regional-free survival (local or regional recurrence, death from RCC). In the MA setting: kidney cancer-specific survival (death from RCC or protocol treatment) and progression-free survival (death from RCC, local, regional, or metastatic progression). CONCLUSIONS: The consensus method revealed that intermediate end points have not been well defined, because all of the selected end points had at least one event definition for which no consensus was obtained. These clarified definitions of TEE should become standard practice in all RCC clinical trials, thus facilitating reporting and increasing precision in between trial comparisons.

The frontal branch of the facial nerve: can we define a safety zone?

PURPOSE: The temporal branch of the facial nerve, a particularly important branch in facial expression, is commonly exposed to surgical trauma. The frontal branch is the most important branch of the temporal branch in the clinical point of view. However, it does not really define in the international nomenclature. The objective of this study was to clearly identify this branch, to perform a cartography of the crossing areas of this branch; and therefore to define statistically a zone of safety within the fronto-temporal region. METHOD: We used 12 fresh cadavers to perform 24 facial nerve dissections. After the identification of the facial nerve, the branches of the temporofacial trunk were identified, dissected and followed till their penetration. We measured the relationship of the frontal branch with the zygomatic arch, temporal vessels and lateral border of the orbit. We conducted a statistical study to assess the risk of injury of this branch within the temporal region. RESULTS: We observed an important variability in the distribution of this branch in the temporal region. We defined three zones of decreasing safety at the level of three interest landmarks: at the level of the inferior part of the zygomatic arch, we estimated an elevated risk of nerve injury (>85%) from 22.6 to 26.06 mm in front of the tragus; at the level of the superior part of the zygomatic arch, we estimated an elevated risk of nerve injury (>85%) from 27.46 to 30.43 mm in front of the tragus; at the level of the lateral border of the orbit, we estimated an elevated risk of nerve injury (>85%) from 16.20 to 19.17 mm behind this landmark. CONCLUSIONS: There exists no real area of anatomical safety in the temporal region. It seems, however, possible to define areas of relative safety that would be of great help for the surgeon or the morphologist wishing to approach pathologies of this region.

What risk of prostate cancer led urologist to recommend prostate biopsies?

OBJECTIVE: The aim of this study was to estimate the risk of prostate cancer that led urologists to perform prostate biopsies. PATIENTS AND METHODS: Eight hundred and eight patients had prostate biopsies in 5 tertiary centres in 2010. Following data were collected: age, PSA, DRE, prostate volume, negative prior prostate biopsy and estimated life expectancy (> or <10 years). The risk of prostate cancer was calculated by validated nomogram of PCPT-CRC and SWOP-PRI and correlated with pathological biopsy results. RESULTS: In final analysis, 625 patients were included, 568 (90.9%) had a life expectancy greater than 10 years. Prostate cancer was found in 291 (46.6%) cases. These patients were older (66.7 ± 6.8 vs 64.3 ± 5.6 years, P < 0.001), had higher PSA values (10 ± 7.9 vs 7.7 ± 4.3 ng/mL, P < 0.0001) and the prostate volume decreased (43.8 ± 19.8 vs 51.3 ± 20.7 mL, P < 0.0001) compared with healthy subjects. Digital Rectal Examination was more frequently suspicious in the group of patients with prostate cancer (43.6% vs 18.9%, P < 0.0001). Risk of prostate cancer estimated was 50.6 ± 14% for PCPT-CRC without ATCD, 56.2 ± 12.8% with PCPT-CRC ATCD and 31.2 ± 17.3% for SWOP-PRI. The likelihood of high-risk prostate cancer was 22.4 ± 16.9% with the PCPT-CRC, and 14.8 ± 18.2% with SWOP-PRI. CONCLUSION: This study showed that urologists performed prostate biopsies when the risk of cancer was high.

Dermatofibrosarcoma protuberans: margins reduction using slow-Mohs micrographic surgery. Experience with 35 patients.

INTRODUCTION: Dermatofibrosarcoma protuberans (DFSP) is a potentially malignant dermal mesenchymal tumour with a high risk of local recurrence. DFSP presents a sprawling appearance whose complete excision requires important margins. DFSP was initially resected with a 5cm excision margins, and more recently 3cm then 2cm margins were recommended. Mohs micrographic surgery (MMS) helps reduce these margins thanks to a 3-dimensional excision around the tumour, which is analysed in its entirety. We used the modified MMS called slow-MMS and tried every time it was possible to perform direct closure. METHODS: Thirty-five patients presenting a DFSP between 2004 and 2013 within the Plastic Surgery unit at Claudius Regaud Institute were included in this retrospective study. The patients were treated with slow-MMS using paraffin-embedded sections. RESULTS: One surgery was necessary for 72% of patients. For 17%, we had to perform a second surgery, and for 11% a third one. Our median clinical excision margins was 17mm (range 9.0:30.0). After a median follow-up of 46 months (range 35.2:60.2), we didn't observe any recurrence. Only one case required a local flap; for the others, the loss of substance was resolved with a direct closure. CONCLUSION: Slow-MMS enabled a local control of the margins without recurrence at 46 months in our series. Besides, it helps performing smaller margins than wide excision and thus preserving the tissues. In our opinion, this is the treatment of choice regarding DFSP for which tissue sparing is essential. It seems particularly appropriate near functional areas or on the face.

Clinical characteristic and survival outcomes of patients with advanced NSCLC according to KRAS mutational status in the French real-life ESME cohort.

PURPOSE: The RAS/MEK signaling pathway is essential in carcinogenesis and frequently altered in non-small-cell lung cancer (NSCLC), notably by KRAS mutations (KRASm) that affect 25%-30% of non-squamous NSCLC. This study aims to explore the impact of KRASm subtypes on disease phenotype and survival outcomes. PATIENTS AND METHODS: We conducted a retrospective analysis of the French Epidemiological Strategy and Medical Economics database for advanced or metastatic lung cancer from 2011 to 2021. Patient demographics, histology, KRASm status, treatment strategies, and outcomes were assessed. RESULTS: Of 10 177 assessable patients for KRAS status, 17.6% had KRAS p.G12C mutation, 22.6% had KRAS non-p.G12C mutation, and 59.8% were KRASwt. KRASm patients were more often smokers (96.3%) compared with KRASwt (85.8%). A higher proportion of programmed death-ligand 1 ≥50% was found for KRASm patients: 43.5% versus 38.0% (P < 0.01). KRASm correlated with poorer outcomes. First-line median progression-free survival was shorter in the KRASm than the KRASwt cohort: 4.0 months [95% confidence interval (CI) 3.7-4.3 months] versus 5.1 months (95% CI 4.8-5.3 months), P < 0.001. First-line overall survival was shorter for KRASm than KRASwt patients: 12.6 months (95% CI 11.6-13.6 months) versus 15.4 months (95% CI 14.6-16.2 months), P = 0.012. First-line chemoimmunotherapy offered better overall survival in KRAS p.G12C (48.8 months) compared with KRAS non-p.G12C (24.0 months) and KRASwt (22.5 months) patients. Second-line overall survival with immunotherapy was superior in the KRAS p.G12C subgroup: 12.6 months (95% CI 8.1-18.6 months) compared with 9.4 months (95% CI 8.0-11.4 months) for KRAS non-p.G12C and 9.6 months (8.4-11.0 months) for KRASwt patients. CONCLUSION: We highlighted distinct clinical profiles and survival outcomes according to KRASm subtypes. Notably KRAS p.G12C mutations may provide increased sensitivity to immunotherapy, suggesting potential therapeutic implications for sequencing or combination of therapies. Further research on the impact of emerging KRAS specific inhibitors are warranted in real-world cohorts.

Incidence and outcome of brain and/or leptomeningeal metastases in HER2-low metastatic breast cancer in the French ESME cohort.

BACKGROUND: Breast cancer (BC) is the second most common cancer that metastasizes to the brain. Particularly up to half of patients with human epidermal growth factor receptor 2 (HER2)-positive (HER2+) metastatic breast cancer (mBC) may develop brain metastases over the course of the disease. Nevertheless, little is known about the prevalence and the outcome of brain and leptomeningeal metastases (BLMM) in HER2-low BC. We compared the cumulative incidence of BLMM and associated outcomes among patients with HER2-low, HER2-negative (HER2-) and HER2+ mBC. PATIENTS AND METHODS: This cohort study was conducted from the Epidemiological Strategy and Medical Economics (ESME) mBC database and included patients treated for mBC between 2012 and 2020 across 18 French comprehensive cancer centers and with known HER2 and hormone receptor (HR) status. The cumulative incidence of BLMM after metastatic diagnosis was estimated using a competing risk methodology with death defined as a competing event. RESULTS: 19 585 patients were included with 6118 (31.2%), 9943 (50.8%) and 3524 (18.0%) being HER2-low, HER2- and HER2+ mBC, respectively. After a median follow-up of 48.6 months [95% confidence interval (CI) 47.7-49.3 months], BLMM were reported in 4727 patients: 1192 (25.2%) were diagnosed with BLMM at first metastatic diagnosis and 3535 (74.8%) after metastatic diagnosis. Multivariable analysis adjusted for age, histological grade, metastases-free interval and HR status showed that the risk of BLMM at metastatic diagnosis was similar in patients with HER2- compared to HER2-low mBC [odds ratio (OR) (95% CI) 1.00 (0.86-1.17)] and higher in those with HER2+ compared to HER2-low [OR (95% CI) 2.23 (1.87-2.66)]. Similar results were found after metastatic diagnosis; the risk of BLMM was similar in HER2- compared to HER2-low [subdistribution hazard ratio (sHR) (95% CI) 1.07 (0.98-1.16)] and higher in the HER2+ group [sHR (95% CI) 1.56 (1.41-1.73)]. CONCLUSIONS: The prevalence and evolution of BLMM in HER2-low mBC are similar to those in patients with HER2- tumors. In contrast to patients with HER2+ mBC, the prognosis of BLMM remains dismal in this population.

Accuracy of intraoperative pathological examination of SLN in cervical cancer.

OBJECTIVE: Early cervical cancer patients with pelvic lymph node metastasis do not benefit from radical hysterectomy. Assessment of the SLN status is thus crucial before deciding to perform a radical hysterectomy as opposed to aortic dissection only followed by definitive radiation therapy. Accuracy of frozen section of SLN has been questioned and deserves further investigation. METHODS: Stage IA-IB1 cervical cancer patients who underwent SLN then full pelvic dissection at the Claudius Regaud Cancer Center in Toulouse, France, were included. RESULTS: At least one SLN was identified in all 94 patients. Bilateral detection rate was 80.8%. Ectopic drainage area was found in 19 patients (20.2%). Sentinel lymph node involvement was found in 11 patients (11.7%). Sensitivity and NPV of frozen section pathological examination for the detection of macrometastatic disease was 100%, sensitivity for the detection of macro and micrometastatic disease, excluding ITC, was 88.9%, and NPV was 98.8%. Micrometastasis and isolated tumor cells (ITC) undetected at frozen section examination were found in 1 patient (1.06%) and 2 lymph nodes (1.24%), and in 2 patients (2.13%) and 2 lymph nodes (1.24%), respectively. Final pathology sensitivity of SLN was 100% for both macro and micrometastatic disease, including ITC. CONCLUSION: In our institution, intraoperative frozen examination of SLN accurately predicts the status of pelvic lymph nodes and is effective for selecting intraoperatively the group of patients who benefit from radical hysterectomy. In addition, our results suggest that patients with small tumors and bilateral detection of SLN can be spared full pelvic lymphadenectomy.

Reduced risk of secondary primary extra pulmonary cancer in advanced/metastatic lung cancer patients treated with immune checkpoint inhibitors.

BACKGROUND: Lung cancer survivors are at high risk of developing a second primary cancer (SPC). We explored the Unicancer Epidemiology Strategy Medical-Economics for advanced or metastatic lung cancer (AMLC) database to assess the impact of immune checkpoint inhibitors (ICI) on the risk of SPC in patients with advanced/metastatic lung cancer. PATIENTS AND METHODS: This retrospective study used data from patients with AMLC, with treatment initiated between January 1st 2015 and December 31st 2018. Patients with lung cancer as the second primary cancer were excluded and a 6-months landmark threshold was applied to exclude patients with synchronous SPC, patients dead without SPC or with a follow-up inferior to 6 months. A propensity score (PS) was calculated on the following baseline covariates: Age at locally advanced or metastatic diagnosis, sex, smoking status, metastatic status, performance status and histological type. The inverse probability of treatment weighting approach was used on the analyses aiming to assess the impact of ICI administered for AMLC, on the risk of occurrence of SPC. RESULTS: Among the 10 796 patients, 148 (1.4%) patients had a diagnosis of SPC in a median interval of 22 (min-max: 7-173) months. All the patients (100%) with locally advanced or metastatic LC received at least one systemic treatment including (chemotherapy regimen (n = 9 851, 91.2%); ICI (n = 4 648, 43.0%); targeted treatment (n = 3 500; 32.4%). 40 (0.9%) SPC were reported in the 4 648 patients with metastatic LC treated with ICI vs 108 (1.7%) out of the 6 148 who did not receive immunotherapy (p < 0.0001). The multivariate analysis identified that treatment with ICI in patients with AMLC is associated with a reduced risk of SPC (HR = 0.40, 95% CI 0.27-0.58). CONCLUSION: Treatment with ICI in AMLC patients was associated with a significantly reduced risk of SPC. Prospective studies are required to confirm these results.