Prediction of Benefit From Adjuvant Pertuzumab by 80-Gene Signature in the APHINITY (BIG 4-11) Trial.

PURPOSE: At the primary analysis, the APHINITY trial reported a statistically significant but modest benefit of adding pertuzumab to standard adjuvant chemotherapy plus trastuzumab in patients with histologically confirmed human epidermal growth factor receptor 2 (HER2)-positive early-stage breast cancer. This study evaluated whether the 80-gene molecular subtyping signature (80-GS) could identify patients within the APHINITY population who derive the most benefit from dual anti-HER2 therapy. METHODS: In a nested case-control study design of 1,023 patients (matched event to control ratio of 3:1), the 80-GS classified breast tumors into functional luminal type, HER2 type, or basal type. Additionally, 80-GS distinguished tumor subtypes that exhibited a single-dominant functional pathway versus tumors with multiple activated pathways. The primary end point was invasive disease-free survival (IDFS). Hazard ratios (HRs) were evaluated by Cox regression. After excluding patients without appropriate consent and those with missing data, 964 patients were included. RESULTS: The 80-GS classified 50% (n = 479) of tumors as luminal type, 28% (n = 275) as HER2 type, and 22% (n = 209) as basal type. Most luminal-type tumors (86%) displayed a single-activated pathway, whereas 49% of HER2-type and 42% of basal-type tumors were dual activated. There was no significant difference in IDFS among different conventional 80-GS subtypes (single- and dual-activated subtypes combined). However, basal single-subtype tumors were significantly more likely to have an IDFS event (hazard ratio, 1.69 [95% CI, 1.12 to 2.54]) compared with other subtypes. HER2 single-subtype tumors displayed a trend toward greater beneficial effect on the addition of pertuzumab (hazard ratio, 0.56 [95% CI, 0.27 to 1.16]) compared with all other subtypes. CONCLUSION: The 80-GS identified subgroups of histologically confirmed HER2-positive tumors with distinct biological characteristics. Basal single-subtype tumors exhibit an inferior prognosis compared with other subgroups and may be candidates for additional therapeutic strategies. Preliminary results suggest patients with HER2-positive, genomically HER2 single-subtype tumors may particularly benefit from added pertuzumab, which warrants further investigation.

Surgery of the primary tumor in patients with de novo metastatic breast cancer: a nationwide population-based retrospective cohort study in Belgium.

PURPOSE: We aimed to assess the impact of surgery of primary tumor in overall survival (OS) of women with de novo metastatic breast cancer. METHODS: Nationwide, population-based retrospective cohort study of women diagnosed with de novo metastatic breast cancer in Belgium, between Jan/2010-Dec/2014. Data was obtained from the Belgian Cancer Registry and administrative databases. "Surgery" group was defined by surgery of primary tumor up to nine months after diagnosis. We excluded women who did not receive systemic treatment or did not complete nine months follow-up after diagnosis. All the subsequent analyses reporting on overall survival and the stratified outcome analyses were performed based on this nine-month landmark cohort. OS was estimated using Kaplan-Meier method and compared using adjusted Cox proportional hazards models controlling for confounders with 95% confidence intervals (CI). We performed a stratified analysis according to surgery timing and a propensity score matching analysis. RESULTS: 1985 patients, 534 (26.9%) in the "Surgery" and 1451 (73.1%) in the "No Surgery" group. Patients undergoing surgery were younger (p < 0.001), had better performance status (PS) (p < 0.001), and higher proportion of HER2-positive and triple-negative breast cancer (p = 0.012). Median follow-up was 86.0 months (82.6-88.5). Median OS was 60.1 months (57.1-68.2) in the "Surgery" vs. 41.9 months (39.8-44.2) in the "No Surgery" group (adjusted HR 0.56; 0.49-0.64). OS was similar when surgery was performed upfront or after systemic treatment. Propensity score matching analysis confirmed the same findings. CONCLUSION: Among patients receiving systemic treatment for de novo metastatic breast cancer and surviving nine months or more, those who received surgery of the primary tumor within nine months of diagnosis have longer subsequent survival than those who did not.

EORTC 1409 GITCG/ESSO 01 - A prospective colorectal liver metastasis database for borderline or initially unresectable diseases (CLIMB): Lessons learnt from real life. From paradigm to unmet need.

AIM: Multidisciplinary management of metastatic colorectal liver metastases (CRLM) is still challenging. To assess postoperative complications in initially unresectable or borderline resectable CRLM, the prospective EORTC-1409 ESSO 01-CLIMB trial capturing 'real-life data' of European centres specialized in liver surgery was initiated. MATERIAL AND METHODS: A total of 219 patients were registered between May 2015 and January 2019 from 15 centres in nine countries. Eligible patients had borderline or initially unresectable CRLM assessed by pre-operative multidisciplinary team discussion (MDT). Primary endpoints were postoperative complications, 30-day and 90-days mortality post-surgery, and quality indicators. We report the final results of the 151 eligible patients that underwent at least one liver surgery. RESULTS: Perioperative chemotherapy with or without targeted treatment were administered in 100 patients (69.4%). One stage resection (OSR) was performed in 119 patients (78.8%). Two stage resections (TSR, incl. Associating Liver Partition and Portal Vein Ligation for Staged hepatectomy (ALPPS)) were completed in 24 out of 32 patients (75%). Postoperative complications were reported in 55.5% (95% CI: 46.1-64.6%), 64.0% (95% CI: 42.5-82%), and 100% (95% CI: 59-100%) of the patients in OSR, TSR and ALPPS, respectively. Post-hepatectomy liver failure occurred in 6.7%, 20.0%, and 28.6% in OSR, TSR, and ALPPS, respectively. In total, four patients (2.6%) died after surgery. CONCLUSION: Across nine countries, OSR was more often performed than TSR and tended to result in less postoperative complications. Despite many efforts to register patients across Europe, it is still challenging to set up a prospective CRLM database.

A leap towards changing gender dynamics in oncology leadership - An ESSO-EYSAC initiative.

Despite the importance of diversity for the success and survival of biological and social systems, women are underrepresented in leadership positions, particularly in the medical field. Data from seven internationally renowned academic associations in surgical, medical, and radiation oncology show that women's representation in leadership roles is only 11%, with no individual society exceeding 20%. Possible justifications for the underrepresentation of women include unconscious biases and societal norms. Fortunately, a notable development in the form of an increased number of women attaining leadership positions in many major professional societies has emerged over recent times, thereby reflecting a positive transformation in the direction of gender equality. The authors recommend organizational interventions such as mentorship, leadership development programs, and national-level initiatives with global collaboration. The oncology community must promote a culture of cooperation and gender equality to ensure equitable opportunities for women in all aspects of life, including professional hierarchy.

Current practice in assessment and management of malnutrition in surgical oncology practice - An ESSO-EYSAC snapshot analysis.

INTRODUCTION: Malnutrition is common in patients suffering from malignant diseases and has a major impact on patient outcomes. Prevention and early detection are crucial for effective treatment. This study aimed to investigate current international practice in the assessment and management of malnutrition in surgical oncology departments. MATERIAL AND METHODS: The survey was designed by European Society of Surgical Oncology (ESSO) and ESSO Young Surgeons and Alumni Club (EYSAC) Research Academy as an online questionnaire with 41 questions addressing three main areas: participant demographics, malnutrition assessment, and perioperative nutritional standards. The survey was distributed from October to November 2021 via emails, social media and the ESSO website to surgical networks focussing on surgical oncologists. Results were collected and analysed by an independent team. RESULTS: A total of 156 participants from 39 different countries answered the survey, reflecting a response rate of 1.4%. Surgeons reported treating a mean of 22.4 patients per month. 38% of all patients treated in surgical oncology departments were routinely screened for malnutrition. 52% of patients were perceived as being at risk for malnutrition. The most used screening tool was the "Malnutrition Universal Screening Tool" (MUST). 68% of participants agreed that the surgeon is responsible for assessing preoperative nutritional status. 49% of patients were routinely seen by dieticians. In cases of severe malnutrition, 56% considered postponing the operation. CONCLUSIONS: The reported rate of malnutrition screening by surgical oncologists is lower than expected (38%). This indicates a need for improved awareness of malnutrition in surgical oncology, and nutritional screening.

Impact of Age on Clinical Outcomes and Efficacy of Adjuvant Dual Anti-HER2 Targeted Therapy.

BACKGROUND: Young age at breast cancer (BC) diagnosis has historically been a rationale for overtreatment. Limited data with short follow-up exist on the prognostic value of age at diagnosis in HER2-positive BC and the benefit of anti-HER2 therapy in young patients. METHODS: APHINITY (NCT01358877) is an international, placebo-controlled, double-blind randomized phase III trial in HER2-positive early BC patients investigating the addition of pertuzumab to adjuvant chemotherapy plus trastuzumab. The prognostic and predictive value of age on invasive disease-free survival (IDFS) as continuous and dichotomous variable (aged 40 years or younger and older than 40 years) was assessed. A subpopulation treatment effect pattern plot analysis was conducted to illustrate possible treatment-effect heterogeneity based on age as a continuous factor. RESULTS: Of 4804 included patients, 768 (16.0%) were aged 40 years or younger at enrollment. Median follow-up was 74 (interquartile range = 62-75) months. Young age was not prognostic either as dichotomous (hazard ratio [HR] = 1.06, 95% confidence interval [CI] = 0.84 to 1.33) or continuous (HR = 1.00, 95% CI = 1.00 to 1.01) variable. Lack of prognostic effect of age was observed irrespective of hormone receptor status and treatment arm. No statistically significant interaction was observed between age and pertuzumab effect (Pinteraction = 0.61). Adding pertuzumab improved IDFS for patients in the young (HR = 0.86, 95% CI = 0.56 to 1.32) and older (HR = 0.75, 95% CI = 0.62 to 0.92) cohorts. Similar results were observed irrespective of hormone receptor status. Subpopulation treatment effect pattern plot analysis confirmed the benefit of pertuzumab in 6-year IDFS across age subpopulations. CONCLUSIONS: In patients with HER2-positive early BC treated with modern anticancer therapies, young age did not demonstrate either prognostic or predictive value, irrespective of hormone receptor status.

Six-year absolute invasive disease-free survival benefit of adding adjuvant pertuzumab to trastuzumab and chemotherapy for patients with early HER2-positive breast cancer: A Subpopulation Treatment Effect Pattern Plot (STEPP) analysis of the APHINITY (BIG 4-11) trial.

AIM: The APHINITY trial showed that adding adjuvant pertuzumab (P) to trastuzumab and chemotherapy, compared with adding placebo (Pla), significantly improved invasive disease-free survival (IDFS) for patients with HER2+ early breast cancer both overall and for the node-positive (N+) cohort. We explored whether adding P could benefit some N- subpopulations and whether to consider de-escalation for some N+ subpopulations. METHODS: Subpopulation Treatment Effect Pattern Plot (STEPP) is an exploratory, graphical method that plots estimates of treatment effect for overlapping patient subpopulations defined by a covariate of interest. We used STEPP to estimate Kaplan-Meier differences in 6-year IDFS percentages (P minus Pla: Δ ± standard error [SE]), both overall and by nodal status, for overlapping subpopulations defined by (1) a clinical composite risk score, (2) tumour infiltrating lymphocytes (TILs) percentage, and (3) human epidermal growth factor receptor 2 (HER2) FISH copy number. Because of multiplicity, a Δ of at least three SE is required to warrant attention. RESULTS: The average absolute gains in 6-year IDFS percentages were 2.8 ± 0.9 overall; 4.5 ± 1.2 for N+ and 0.1 ± 1.1 for N-. Largest gains were for patients with intermediate clinical composite risk (5.3 ± 1.9 overall; 6.9 ± 2.3 N+; 4.0 ± 3.0 N-), highest TILs percentage (6.3 ± 1.7 overall; 7.4 ± 2.4 N+; 3.2 ± 1.7 N-), and intermediate HER2 copy number (2.8 ± 1.9 overall; 7.4 ± 2.5 N+; -1.3 ± 1.9 N-), but clear evidence indicating a pattern of differential subpopulation treatment effects was lacking. CONCLUSIONS: STEPP plots for N- did not identify subpopulations clearly benefiting from adding P, and those for N+ did not identify subpopulations warranting de-escalation. TILs percentage appeared to be more predictive of P treatment effect than clinical composite risk score. TRIAL REGISTRATION: clinicaltrials.gov Identifier NCT01358877.

Standards in surgical training in advanced pelvic malignancy across Europe and beyond - A Snapshot analysis.

INTRODUCTION: Multimodal treatment of patients with advanced pelvic malignancies (APM) is challenging and surgical expertise is usually concentrated in highly specialised centres. Given significant regional variation in APM surgery, surgical training represents a cornerstone in standardising and future-proofing of this complex therapy. The aim of this study was to describe the availability and current satisfaction levels with surgical training for APM. MATERIAL AND METHODS: An online questionnaire was developed and distributed through the Redcap© platform with 32 questions addressing participant and institution demographics, and training in APM surgeries. The survey was electronically disseminated in 2021 to surgical networks across Europe including all specialities treating APM via the European Society of Surgical Oncology (ESSO). All statistical analysis were performed using R. RESULTS: The survey received 280 responses from surgeons across 49 countries, representing general surgery (36%), surgical oncology (30%), gynaeoncology (15%), colorectal surgery (14%) and urology (5%). Fifty-three percent of participants report performing >25 APM procedures/year. Respondents were departmental chiefs (12%), consultants (34%), specialist surgeons (40%) and fellows (15%). 34% were happy/very happy with their training with 70% satisfaction about their exposure to surgical procedures. Respondents reported a lack of standardised training (72%), monitoring tools (41%) and mentorship (56%). 57% rated attended courses as useful for training, while 80% rated visiting expert centres as useful. CONCLUSION: This study has identified a learning need for improved structured training in APM, with low current satisfaction levels with exposure to APM training. Organisations such as ESSO provide an important platform for visiting expert centres, courses, and structured training.

Comprehensive Review of Fluorescence Applications in Gynecology.

Since the introduction of indocyanine green (ICG) as a fluorophore in near-infrared imaging, fluorescence visualization has become an essential tool in many fields of surgery. In the field of gynecology, recent new applications have been proposed and found their place in clinical practice. Different applications in gynecology were investigated, subcategorized, and overviewed concerning surgical applications and available dyes. Specific applications in which fluorescence-guided surgery was implemented in gynecology are described in this manuscript-namely, sentinel node biopsy, mesometrium visualization, angiography of different organs, safety issues in pregnant women, ureters visualization, detection of peritoneal metastases, targeted fluorophores for cancer detection, fluorescent contamination hysterectomy, lymphography for lower limb lymphedema prevention, tumor margin detection, endometriosis, and metastases mapping. With evolving technology, further innovative research on the new applications of fluorescence visualization in cancer surgery may help to establish these techniques as standards of high-quality surgery in gynecology. However, more investigations are necessary in order to assess if these innovative tools can also be effective to improve patient outcomes and quality of life in different gynecologic malignancies.

Genomic and Transcriptomic Analyses of Breast Cancer Primaries and Matched Metastases in AURORA, the Breast International Group (BIG) Molecular Screening Initiative.

AURORA aims to study the processes of relapse in metastatic breast cancer (MBC) by performing multi-omics profiling on paired primary tumors and early-course metastases. Among 381 patients (primary tumor and metastasis pairs: 252 targeted gene sequencing, 152 RNA sequencing, 67 single nucleotide polymorphism arrays), we found a driver role for GATA1 and MEN1 somatic mutations. Metastases were enriched in ESR1, PTEN, CDH1, PIK3CA, and RB1 mutations; MDM4 and MYC amplifications; and ARID1A deletions. An increase in clonality was observed in driver genes such as ERBB2 and RB1. Intrinsic subtype switching occurred in 36% of cases. Luminal A/B to HER2-enriched switching was associated with TP53 and/or PIK3CA mutations. Metastases had lower immune score and increased immune-permissive cells. High tumor mutational burden correlated to shorter time to relapse in HR+/HER2- cancers. ESCAT tier I/II alterations were detected in 51% of patients and matched therapy was used in 7%. Integration of multi-omics analyses in clinical practice could affect treatment strategies in MBC. SIGNIFICANCE: The AURORA program, through the genomic and transcriptomic analyses of matched primary and metastatic samples from 381 patients with breast cancer, coupled with prospectively collected clinical data, identified genomic alterations enriched in metastases and prognostic biomarkers. ESCAT tier I/II alterations were detected in more than half of the patients.This article is highlighted in the In This Issue feature, p. 2659.

Treatment patterns in older patients with locally advanced head and neck squamous cell carcinoma: Results from an EORTC led survey.

OBJECTIVES: We aimed to assess patterns of care delivered to older patients with locally advanced head and neck squamous cell carcinoma (LA-HNSCC), and to analyze the use of geriatric assessment (GA) and assessment of quality of life (QoL). MATERIALS AND METHODS: Members of the head and neck cancer group and the older task force of the European Organisation for Research and Treatment of Cancer (EORTC), members the European Head and Neck Society and members of national groups in Europe were asked to complete a questionnaire about treatment delivered, use of GA, and QoL assessment in older patients with LA-HNSCC. RESULTS: Investigators from 111 centers replied, including 90 (81.1%) academic centers, 16 (14.4%) community hospitals, and 5 (4.5%) private clinics. Large differences in treatment patterns were found. For instance, for oropharyngeal carcinoma, one third of the centers indicated that they treat <5% of older patients with chemoradiation, while 18 centers (16.2%) treat >40% of older patients with chemoradiation. Fourteen centers (12.6%) routinely perform GA, while 43 centers (38.7%) never do, and 39 centers (35.1%) sometimes do. QoL is assessed on a routine basis in one fifth of the centers. CONCLUSIONS: Large differences exist across institutions in the patterns of care delivered to older patients with LA-HNSCC. Prospective studies are required to learn how GA can guide treatment decisions, and how QoL and treatment outcome can be improved. For that, consensus on standard of care is essential.

Road Map to Safe and Well-Designed De-escalation Trials of Systemic Adjuvant Therapy for Solid Tumors.

An important challenge in the field of cancer is finding the balance between delivering effective treatments and avoiding adverse effects and financial toxicity caused by innovative, yet expensive, drugs. To address this, several treatment de-escalation trials have been conducted, but only a few of these have provided clear answers. A few trials had poor accrual or had design flaws that led to conflicting results. Members of the Breast International Group (BIG) and North American Breast Cancer Group (NABCG) believe the way forward is to understand the lessons from these trials and listen more carefully to what truly matters to our patients. We reviewed several adjuvant trials of different cancer types and developed a road map for improving the design and implementation of future de-escalation trials. The road map incorporates patients' insights obtained through focused group discussions across the BIG-NABCG networks. Considerations for the development of de-escalation trials for systemic adjuvant treatment, including noninferiority trial design, choice of end points, and prioritization of a patient's perspectives, are presented in this consensus article.

Building a collaboration to improve surgical research through EORTC/ESSO 1409-CLIMB study: A prospective liver metastasis database with an integrated quality assurance program.

The challenges of conducting surgical oncology trials have resulted to low quantity and poor quality research [1,2]. Considering the definitive role of surgery to offer cure, immediate response to improve surgical research is needed [3]. The European Organization for Research and Treatment of Cancer (EORTC) and the European Society of Surgical Oncology (ESSO) share the vision to achieve excellent surgical research and care for cancer patients. Building on their complimentary expertise, they embarked on a pilot project to map out challenges and initiate a sustainable collaboration to advance cancer surgery research in Europe. This pilot project is EORTC-ESSO 1409 GITCG/ ESSO-01: A Prospective Colorectal Liver Metastasis Database with an Integrated Quality Assurance Program (CLIMB). This article will describe the challenges, milestones and vision of both organizations in setting up this collaboration.

EORTC-1203-GITCG - the "INNOVATION"-trial: Effect of chemotherapy alone versus chemotherapy plus trastuzumab, versus chemotherapy plus trastuzumab plus pertuzumab, in the perioperative treatment of HER2 positive, gastric and gastroesophageal junction adenocarcinoma on pathologic response rate: a randomized phase II-intergroup trial of the EORTC-Gastrointestinal Tract Cancer Group, Korean Cancer Study Group and Dutch Upper GI-Cancer group.

BACKGROUND: 10-20% of patients with gastric cancer (GC) have HER2+ tumors. Addition of trastuzumab (T) to cisplatin/fluoropyrimidine-based chemotherapy (CT) improved survival in metastatic, HER2+ GC. When pertuzumab (P) was added to neoadjuvant T and CT, a significant increase in histopathological complete response rate was observed in HER2+ breast cancer. This study aims to investigate the added benefit of using both HER2 targeting drugs (T alone or the combination of T + P), in combination with perioperative CT for localized HER2+ GC. METHODS: This is a prospective, randomized, open-label, phase II trial. HER2 status from patients with resectable GC (UICC TNM7 tumor stage Ib-III) will be centrally determined. Two hundred and-fifteen patients from 52 sites in 14 countries will be centrally randomized (1:2:2 ratio) to one of the following treatment arms: 1. Standard: CT alone. CT regimens will be FLOT (5-FU, leucovorin, oxaliplatin, taxotere) CapOx (capecitabine, oxaliplatin) or FOLFOX (5-FU, leucovorin, oxaliplatin) according to investigator's choice in Europe, and cisplatin/capecitabine in Asia. 2. Experimental arm 1: CT as in control group, plus T (8 mg/kg loading dose, followed by 6 mg/kg every 3 weeks) at day 1, independent of CT chosen for 3 cycles of 3 weeks before and after surgery. 3. Experimental arm 2: CT plus T as in experimental arm 1, plus P (840 mg every 3 weeks) on day 1. Adjuvant treatment with T or T + P will continue for 17 cycles in total. Stratification factors are: histology (intestinal/non-intestinal); region (Asia vs Europe); location (GEJ vs non-GEJ); HER2 immunohistochemistry score (IHC 3+ vs IHC 2+/FISH+) and chemotherapy regimen. Primary objective is to detect an increase in the major pathological response rate from 25 to 45% either with CT plus T alone, or with CT plus the combination of T and P. DISCUSSION: Depending on the results of the INNOVATION trial, the addition of HER2 targeted treatment with either T or T and P to CT may inform future study designs or become a standard in the perioperative management HER2+ GC. TRIAL REGISTRATION: This article reports a health care intervention on human participants and was registered on July 10, 2014 under ClinicalTrials.gov identifier: NCT02205047 ; EudraCT: 2014-000722-38.

Responding to the challenges of international collaborations between the east and the west - report of the first JCOG-EORTC symposium and a perspective from young JCOG and EORTC investigators.

International/intercontinental collaboration is necessary to set up new innovative clinical trials for cancer treatment. However, the infrastructure, especially Asia-Europe academic partnerships, to enable such collaboration has not been fully structured and differences and similarities between the research groups have not been well studied. In 2015, collaboration started between the biggest cancer research organizations in Asia and EU, Japan Clinical Oncology Group (JCOG) and European Organisation for Research and Treatment of Cancer (EORTC). Following the first pilot collaboration study, the first scientific symposium took place in December 2017 in Tokyo. Before the symposium, a working visit for EORTC investigators from the Early Career Investigator initiative (ECI), willing to develop projects within the JCOG-EORTC partnership, was held. In addition to the digest of the working visit and symposium, we aimed to describe the differences and similarities between the two groups and to identify key factors for collaboration from the perspective of the young investigators of the networks. These findings are described in this article.

Parenchymal sparing surgery brings treatment of colorectal liver metastases into the precision medicine era.

The treatment of advanced colorectal liver metastases (CRLMs) follows the biphasic pattern characteristic of oncological surgery. A phase of escalation-the therapeutic aggressiveness-is followed by a phase of de-escalation aimed at decreasing the morbidity, while preserving the gains in survival. From a maximum of three lesions, the rule no longer limits the number, provided the intervention does not cause lethal liver failure. Technically feasible non-anatomical resections, two-stage hepatectomies, portal vein obliteration and so forth, have pushed the boundaries of surgery far. However, the impact and the biology of metastatic processes have been long ignored. Parenchymal sparing surgery (PSS) is a de-escalation strategy that targets only metastasis by minimising the risk of stimulating tumour growth, while enabling iterative interventions. Reducing the loss of healthy parenchyma increases the tolerance of the liver to interval chemotherapy. Technically, PSS could use any type of hepatectomy, providing it is centred on the metastatic load alongside intraoperative ablation. The PSS concept sometimes wrongly comes across as a debate between minor versus major hepatectomies. Hence, we propose a clear definition, both quantitative and qualitative, of what PSS is and what it is not. Conversely, the degree of selectivity of PSS as a percentage of the volume of resected metastases versus the volume of total liver removed has not been stopped to date and should be the subject of prospective studies. Ultimately, the treatment of advanced CRLMs, of which PSS is a part, needs to be personalised by the multidisciplinary team by adapting its response to each new recurrence.