Node-negative Tumors Research Articles

De-Escalating Treatment Strategies for Patients with Human Epidermal Growth Factor Receptor-2 (HER2)-Positive Early-Stage Breast Cancer.

Almost one-fifth of breast cancer cases express Human Epidermal Growth Factor-2 (HER2), and such expression is associated with highly proliferative tumors and poor prognosis. The introduction of anti-HER2 therapies has dramatically changed the natural course of this aggressive subtype of breast cancer. However, anti-HER2 therapy can be associated with substantial toxicities, mostly cardiac, and high cost. Over the past few years, there has been growing interest in de-escalation of anti-HER2 therapies to minimize adverse events and healthcare costs, while maintaining the efficacy of treatment. Data from clinical observations and single-arm studies have eluted to the minimal impact of anti-HER2 therapy in low-risk patients, like those with node-negative and small tumors. Though single-arm, the APT trial, in which patients with node-negative, small tumors received single-agent paclitaxel for 12 cycles plus trastuzumab for 1 year, was a practice-changing study. Several other recently published studies, like the PERSEPHONE trial, have shown more convincing data that 6 months of trastuzumab is not inferior to 12 months, in terms of disease-free survival (DFS), suggesting that de-escalating strategies with shorter treatment may be appropriate for some low-risk patients. Other de-escalating strategies involved an adaptive, response-directed approach, and personalized therapy that depends on tumor genomic profiling.

Impact of young age at diagnosis on survival outcomes in patients with early breast cancer according to tumor subtype: Pooled analysis of 5 randomized clinical trials from the Mammella InterGruppo (MIG) and Gruppo Italiano Mammella (GIM).

523 Background: The incidence of breast cancer (BC) among young patients is increasing. Historically, young age itself has been recognised as a poor prognostic factor for BC. However, there is limited evidence regarding the impact of age at diagnosis and on survival outcomesaccording to tumor subtype. Methods: We collected individual patient (pt)-level data from newly diagnosed stage I to III BC pts participating in 5 randomized clinical trials conducted by Mammella InterGruppo (MIG) and Gruppo Italiano Mammella (GIM) study groups. Patients were categorized into the following age groups based on their age at BC diagnosis: ≤40, 41-50, 51-60, 61-70, >70 years (yr). Multivariable Cox proportional hazards models were used to assess the relationship between age and breast cancer–free interval (BCFI) and breast cancer specific survival (BCSS). Results: 8,338 pts with stage I to III BC were included in the study: 778 (9%) aged ≤40 years, 1629 (20%) 41-50 years, 2,595 (31%) 51-60 years, 2,435 (29%) 61-70 years, and 901 (11%) >70 years. Compared to older, young pts were more likely to have ductal tumors as histology, larger than 2 cm, with nodal involvement, G3 and triple negative or HER2 positive subtypes (p<0.001). With a median follow-up of 9.0 years (IQR 5.5-14.4), 2,161 BCFI and 927 BCSS events were observed in the overall population. Pts ≤40 years at diagnosis had greater risk of reporting BC event (adjusted hazard ratio (adjHR) for BCFI 1.27, 95% CI 0.93-1.74) compared to pts aged 51-60 years (reference group), while pts 41-50 years had a lower risk (adjHR 0.74, 95%CI 0.55-0.99). Pts aged ≤40 years presented some evidence of a lower risk of BCSS events (adjHR 0.80, 95%CI 0.50-1.26) compared to pts aged 51-60 years, while pts aged 41-50 years had the lowest risk (adjHR 0.50, 95%CI 0.32-0.78). There was evidence of interaction between age and tumor subtype, nodal status both for BCFI and BCSS. A significant increase in risk of BC events was observed among pts ≤40 years with hormone-receptor positive/HER2 negative tumors (HR 1.70 for BCFI) and among ≤40 years with node negative tumors (HR for BCFI 2.43). Conclusions: The prognostic significance of young age at diagnosis may vary depending on tumor subtypes and nodal status, indicating poorer outcomes for young pts with hormone-receptor positive/HER2 negative and node negative tumors.

Prevalence and dynamics of circulating tumor DNA (ctDNA) among patients (pts) with HER2+ breast cancer (BC) receiving neoadjuvant paclitaxel/trastuzumab/pertuzumab (THP) in the DAPHNe trial.

588 Background: Neoadjuvant THP may become a new standard for pts with early stage HER2+ BC pending results of large ongoing trials. Although ctDNA persistence in the (neo)adjuvant setting is associated with elevated risk of distant recurrence, the prevalence and dynamics of ctDNA in HER2+ BC are unknown. Methods: On the single-arm phase II DAPHNe trial, pts with stage II-III HER2+ BC received 12 weeks of neoadjuvant THP, followed by surgery and adjuvant systemic therapy (tx) per physicians’ discretion (with no further chemotherapy in case of pCR). Plasma samples were prospectively collected at 4 timepoints: baseline (BL), pre-operatively (pre-op), immediate post-operatively (post-op), and during the final 3 mos of adjuvant HER2-directed tx. ctDNA was measured using NeXT Personal, a tumor-informed assay based on whole-genome sequencing of tumor/normal samples to detect and quantify minimal residual disease (MRD). We assessed the association of MRD with residual cancer burden (RCB) and long-term outcomes. Results: Of 98 pts enrolled in DAPHNe, 50 had at least one plasma sample sequenced with NeXT Personal. Of these 50 pts, the median age was 50 yrs, 92% had clinical stage II and 64% had hormone-receptor positive (HR+) tumors. RCB scores were: RCB 0 (33/50 pts, 66%), RCB I (2/50 pts, 4%), RCB II (14/50 pts, 28%), RCB III (1/50 pts, 2%). With 50 mos median follow-up, there have been no breast cancer recurrences. ctDNA was detected (ctDNA+) at BL in 42/49 pts (92%) (median detected level 210 parts per million (PPM), broad detection range of 36,978 down to 3 PPM, and 34% of detected pts had ctDNA level <100 PPM). All pts with T3/T4 tumors or positive nodes had BL ctDNA+, whereas 91% and 85% of pts with T1/T2 or node-negative tumors, respectively, had BL ctDNA+. Most pts cleared MRD after THP. Rates of ctDNA detection at post-BL timepoints were: 2/49 pts (4%) at pre-op; 2/48 pts (4%) at post-op; and 1/34 pts (3%) at late adjuvant times. Statistical comparison of pts who cleared vs did not clear ctDNA during neoadjuvant THP was not possible given the high rate of ctDNA positivity at BL and the high rate of negativity pre-op. Clinical vignettes of the 5 pts with detectable MRD at any post-BL timepoint are shown (Table). MRD data from additional pts will be presented. Conclusions: In this population of moderate risk (mostly stage II) HER2+ BC pts, 92% were ctDNA+ at BL. Neoadjuvant THP was very effective at clearing MRD, regardless of whether there was residual disease in the breast/nodes or not, consistent with the absence of any BC recurrence in the cohort to date. Clinical trial information: NCT03716180 . [Table: see text]

Abstract PO5-04-10: Clinical and prognostic value of MLN51 (Metastatic lymph node gene 51)/CASC3 (Cancer susceptibility candidate gene 3) in clinical breast cancer, connection with nodal and hormonal receptor status

Abstract Introduction: Metastatic Lymph Node Gene 51 Protein (MLN51) also known as Cancer Susceptibility Candidate Gene 3 Protein (CASC3) or Barentsz (BTZ) is a molecule that was first identified in malignant breast tumours. The CASC3 gene encodes the protein that binds to mRNA and is a key component of the exon junction complex (EJC), playing an important role in the metabolism of mRNA and in cellular recovery after stress responses. It is not clear, however, if MLN51 has a clinical value in assessing the disease progression of breast cancer. Methods: We analysed the transcription expression levels of MLN51 in a cohort of human breast cancer tissues and correlated the expression pattern with clinical outcome, pathological type and hormonal receptor status. Results: High levels of MLN51 was found to be a favourable prognostic indicator for overall survival (p=0.008, Hazard Ratio [HR=0.262]), the prognostic value being independent of other clinical and pathological factors. Likewise, high levels of MLN51 were also a significant and independent predictive factor for disease free survival (DFS) (p=0.003, HR=0.262). It was found that the favourable prediction in both OS and DFS was associated with node positive tumours, with significance with OS (p=0.004), compared in node negative tumours (p=0.143) and to DFS (p=0.001 in node positive compared with p=0.079 in node negative tumours). Levels of MLN51 had a significant correlation with EGFR in both normal and tumour mammary tissues but correlated with Her-2 and Her-3 in tumour tissues only. The prognostic power of MLN51 for DFS was significant in both Her-2 positive and Her-2 negative (p=0.003 and p=0.012) tumours and in ER negative tumours (p=0.003). The prediction for OS by MLN51 was particularly strong for Her-2 positive and ER positive (p=0.007 for both) tumours. Conclusions: MLN51 (CASC3) is a favourable prognostic factor in patients with breast cancer. This is clearly linked to the nodal status and hormone receptor status, particularly ER and HER-2. Citation Format: Binbin Cong, Tracey Martin, Xiaoshan Cao, Robert E Mansel, Eleri Davies, Wen Jiang. Clinical and prognostic value of MLN51 (Metastatic lymph node gene 51)/CASC3 (Cancer susceptibility candidate gene 3) in clinical breast cancer, connection with nodal and hormonal receptor status [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-04-10.

Abstract PO1-01-12: A retrospective cohort study on the effect of adding adjuvant ovarian function suppression to endocrine therapy in premenopausal women with T1-T2 tumor hormone-positive breast cancer on survival and disease recurrence

Abstract Background: Breast cancer is the most common diagnosed cancer in women and is the leading cause of cancer death. Young women diagnosed with breast cancer are at higher rates of adverse outcomes in terms of survival and recurrence. Hormone sensitive breast cancer is the commonest subtype of breast cancer in this group. To date, the standard adjuvant treatment is endocrine therapy for both pre and post-menopausal women. Recent published studies have recommended adding ovarian function therapy to premenopausal women who are at high risk of recurrence. In this study we evaluated the impact of adding adjuvant ovarian function suppression for premenopausal women with small (T1 and T2) hormone receptor positive node negative breast cancer who did not receive any form of chemotherapy on overall survival and disease-free recurrence. Methods: We performed a retrospective study where we evaluated the electronic medical records of 4431 premenopausal women diagnosed with breast cancer in Asan Medical Center in Seoul, South Korea. All the analyzed patients were operated from the period of January 2006 till December 2019. The inclusion criteria were age of 55 and below, T1 and T2 tumors with N0 disease who received selective estrogen receptor modulators (SERM - Tamoxifen) and didn’t receive neo or adjuvant chemotherapy. We compared patients who received SERM (Tam Only) only to patients who received SERM and ovarian function suppression (Tam + OFS) medications. The primary endpoint was overall survival (OS), and the secondary endpoint was mortality and disease-free survival (DFS). We used chi-square test for categorical variables and t-test for continuous variables. The p-value was set as p< 0.05 as statistically significant. Kaplan Meier curve and log rank test were used to analyze the data for overall survival, disease-free survival and mortality. We performed an additional subgroup analysis adjusted to age, tumor size, Ki67%, progesterone receptor, HER2 status and type of operation. Results: There was equal distribution of cases between tamoxifen only group and tamoxifen + OFS group (2121 versus 2310 respectively). The median age in each group was 45 years of age. Tumor size of ≤0.5cm was the commonest in the tamoxifen only group whereas tamoxifen + OFS group had majority of cases with tumor size of 1 - 2cm. Both groups had a Ki-67% of 10-20%. Histologic grade of 2 and nuclear grade of 2 were most commonly representative in the comparing groups. Invasive ductal carcinoma was the most common histological subtype (93-94%) and invasive lobular carcinoma accounted for 5-6% of cases. Regarding immunohistochemistry results, 91-93% of patients were progesterone receptor positive and 68-73% were HER2 negative. The majority underwent breast conserving surgery compared to mastectomy. We have also looked at the pattern of prescribing OFS treatment in the Tamoxifen + OFS group regarding the length of treatment. Nearly 80% of patients received OFS treatment for a period of 1-2 years whereas only 5.2% received < 1 year and 1.8% >2years. After adjusting to age, tumor size, Ki67%, PR receptor and HER2 status, the result was only significant for higher risk of DFS in the TAM + OFS group in Ki67 < 20%. The OFS+TAM had more DFS and mortality events compared to TAM only group. However, the only significant result was the overall survival favoring tamoxifen only group with a p-value of 0.039 and HR of 1.05-7.99. Conclusion: Adding ovarian function suppression to tamoxifen in premenopausal hormone positive node negative T1-T2 tumors didn’t show any benefit in terms of disease-free interval and overall survival. Further studies are advised to assess the benefit of adding ovarian function suppression to this group of patients Table 1: baseline characteristics of Table 2: Disease Free Survival Subgroup Analysis Citation Format: Sarah Al Safi, Hee Jeong Kim, Seonok Kim, Sae Byul Lee, Jisun Kim, Tae-Kyung Yoo, Il-Yong Chung, Beom Seok Ko, Byung Ho Son. A retrospective cohort study on the effect of adding adjuvant ovarian function suppression to endocrine therapy in premenopausal women with T1-T2 tumor hormone-positive breast cancer on survival and disease recurrence [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-01-12.

Abstract PO2-23-02: Results of a prospective randomised multicentre study comparing indocyanine green (ICG) fluorescence combined with a standard tracer versus ICG alone for sentinel lymph node biopsy in early breast cancer: The INFLUENCE Trial

Abstract Background: Use of fluorescence mapping for visualization of lymphatic and nodal tissue for sentinel lymph node biopsy (SNB) reveals high rates of identification (>98%). Studies combining ICG with either blue dye or radioisotope (RI) have shown high levels of concordance (>90%) and comparable performance parameters between ICG and standard tracers for SNB localization. ICG combines many advantages of blue dye and RI without the disadvantages of allergic reactions, staining of skin and surgical tissues along with handling and disposal of radioactivity materials. Moreover, magnetic tracers pose challenges of interference relating to surgical instrumentation and magnetic resonance imaging (MRI). The combination of ICG with a conventional tracer may represent a transition phase and this randomized study evaluates ICG as a sole tracer agent for SNB in early-stage breast cancer. Methods: In a prospective randomized study, 100 patients with unilateral clinically node negative tumours scheduled to undergo routine SNB for core-biopsy proven invasive breast cancer (≤5cm) were identified at multidisciplinary meetings [non-invasive tumours excluded]. All patients had pre-operative axillary ultrasound and breast conserving surgery or mastectomy. Patients were recruited in two cohorts (n=50); cohort 1 was assigned to either ICG [2ml 0.5%] alone (n=25) or combined with RI [Technetium99 nanocolloid, 20MBq] (n=25). Cohort 2 received ICG alone (n=25) or combined with blue dye for SNB localization. The number of nodes whether blue, radioactive, fluorescent or a combination thereof were recorded. Lymphatic and nodal tissue was visualized with a fluorescent camera/detection system. Sensitivity of ICG alone and/or in combination with one or another standard tracer was calculated. The main objective was to assess the performance of ICG alone compared with a standard tracer combination in terms of rates of SNB identification along with procedural node positivity rates. Statistical analysis employed Chi-Square test, Fisher’s Exact test, and logistic regression to determine differences between groups. Results: A total of 100 patients were randomized between March and December 2022 with 3 patients excluded from analysis (non-receipt of treatment allocation). Amongst evaluable patients (n=97), the overall SNB identification rate was 96.9% and by tracer category as follows: ICG alone = 97.9% (46/47); ICG + RI = 100% (25/25); ICG + blue dye = 92% (23/25). For cohort 1, the procedural node positivity rates were 17% for ICG alone and 18% for ICG + RI with corresponding figures of 12% for ICG alone and 20% for ICG + blue dye for cohort 2. Mean procedural node retrieval per case was 2.5 in ICG alone Vs ICG + Blue Dye and 2.3 in ICG alone Vs ICG/RI cohorts. There were no significant differences (p>0.05) in performance of ICG alone or combined with a standard tracer, with ICG alone being non-inferior in terms of procedural and nodal detection rates. Similar conclusions were reached from a secondary analysis adjusting for BMI, age and mode of detection (screening/symptomatic). Conclusion: ICG fluorescence imaging permits real-time visualisation of lymphatics and gives an additional dimension to SNB that appears safe versus the competitive alternatives. These results confirm high sensitivity for fluorescence localisation alone for SNB with comparable performance to combined methods with blue dye or RI. The fluorochrome ICG is reliable as a sole tracer and avoids potential drawbacks of blue dye and RI including staining, allergic reactions, availability and costs. Citation Format: Vassilis Pitsinis, Rahul Kanitkar, Alessio Vinci, Emad Elseedawy, Laura Canna, John R Benson. Results of a prospective randomised multicentre study comparing indocyanine green (ICG) fluorescence combined with a standard tracer versus ICG alone for sentinel lymph node biopsy in early breast cancer: The INFLUENCE Trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-23-02.

Management of early-stage HER2-positive breast cancer and attitudes towards HER2DX test in Spain: insights from a nationwide survey

PurposeThis study aimed to investigate the current therapeutic management of patients with early-stage HER2-positive (HER2+) breast cancer in Spain, while also exploring the perceptions surrounding HER2DX in terms of its credibility, clinical relevance, and impact on therapeutic decision-making. Understanding these aspects is crucial for optimizing treatment strategies and enhancing patient outcomes in the context of HER2+ breast cancer.MethodsAn online questionnaire was conducted by an independent third-party between April and May 2022 across 70 medical oncologists highly specialized in breast cancer management in Spain. The survey included 37 questions regarding treatment decision making in HER2+ early breast cancer.ResultsThe management of patients with HER2+ early breast cancer exhibited a high degree of heterogeneity. Among the interviewed oncologists, 53% would recommend upfront surgery for node negative tumors measuring 1 cm or less. Interestingly, 69% and 56% of interviewers were open to deescalate the duration of adjuvant trastuzumab in pT1a and pT1b N0 tumors, respectively. Certain clinicopathological characteristics, such as high grade, high Ki-67, and young age, influenced the decision to prescribe neoadjuvant treatment for patients with clinical stage 1 disease. In cases where neoadjuvant treatment was prescribed for cT1-2 N0 tumors, there was a wide variation in the choice of chemotherapeutic and anti-HER2 regimens. Regarding the use of adjuvant trastuzumab emtansine (T-DM1) in patients with residual disease after neoadjuvant therapy, there was diversity in practice, and a common concern emerged that T-DM1 might be overtreating some patients. HER2DX, as a diagnostic tool, was deemed trustworthy, and the reported scores were considered clinically useful. However, 86% of interviewees believed that a prospective trial was necessary before fully integrating the test into routine clinical practice.ConclusionIn the context of early-stage HER2+ breast cancer in Spain, a notable diversity in therapeutic approaches was observed. The majority of interviewed medical oncologists acknowledged HER2DX as a clinically valuable test for specific patients, in line with the 2022 SEOM-GEICAM-SOLTI clinical guidelines for early-stage breast cancer. To facilitate the full integration of HER2DX into clinical guidelines, conducting prospective studies to further validate its efficacy and utility was recommended.

Investigating the role of tumour-to-skin proximity in predicting nodal metastasis in breast cancer

BackgroundUnderstanding the factors influencing nodal status in breast cancer is vital for axillary staging, therapy, and patient survival. The nodal stage remains a crucial factor in prognostication indices. This study investigates the relationship between tumour-to-skin distance (in T1–T3 tumours where the skin is not clinically involved) and the risk of nodal metastasis.MethodsWe retrospectively reviewed data from 100 patients who underwent neoadjuvant chemotherapy (NACT). Besides patient demographics and tumour variables, a radiologist retrospectively reviewed pre-operative MRI to measure tumour-to-skin distance. R core packages were used for univariate (χ2 and T-Wilcoxon tests) and bivariate logistic regression statistical analysis.ResultsOf 95 analysable datasets, patients’ median age was 51 years (IQR: 42–61), 97% were symptomatic (rest screen detected), and the median tumour size was 43 mm (IQR, 26–52). On multivariate analysis, increasing invasive tumour size (p = 0.02), ER positivity (p = 0.007) and shorter tumour-to-skin distance (p = 0.05) correlated with nodal metastasis. HER2 was not included in multivariate analysis as there was no association with nodal status on univariate analysis. In node-positive tumours, as tumour size increased, the tumour-to-skin distance decreased (r = − 0.34, p = 0.026). In node-negative tumours, there was no correlation (r = + 0.18, p = 0.23).ConclusionThis study shows that non-locally advanced cancers closer to the skin (and consequent proximity to subdermal lymphatics) are associated with a greater risk of nodal metastasis. Pre-operative identification of those more likely to be node positive may suggest the need for a second-look USS since a higher nodal stage may lead to a change in therapeutic strategies, such as upfront systemic therapy, node marking, and axillary clearance without the need to return to theatre following sentinel node biopsy.

Multiplex Immunofluorescence Captures Progressive Immune Exhaustion with Advancing Penile Squamous Cell Cancer Stage.

Penile squamous cell carcinoma (PSCC) is a rare and deadly malignancy. Therapeutic advances have been stifled by a poor understanding of disease biology. Specifically, the immune microenvironment is an underexplored component in PSCC and the activity of immune checkpoint inhibitors observed in a subset of patients suggests immune escape may play an important role in tumorigenesis. Herein, we explored for the first time the immune microenvironment of 57 men with PSCC and how it varies with the presence of human papillomavirus (HPV) infection and across tumor stages using multiplex immunofluorescence of key immune cell markers. We observed an increase in the density of immune effector cells in node-negative tumors and a progressive rise in inhibitory immune players such as type 2 macrophages and upregulation of the PD-L1 checkpoint in men with N1 and N2-3 disease. There were no differences in immune cell densities with HPV status.

Prognostic factors for aggressiveness in subcentimeter papillary thyroid carcinoma: impact of tumor size and lymph node metastases.

Subcentimeter papillary thyroid carcinoma (sPTC), also known as papillary thyroid microcarcinoma, is associated with a good prognosis and low mortality risk. However, some sPTCs exhibit biologically aggressive characteristics. The aim of this study was to identify factors affecting the prognosis and aggressiveness of sPTC by considering the demographic characteristics of patients with sPTC and the pathologic characteristics of the tumors. The study included 255 patients aged ≥ 18 years who were operated on at Ondokuz Mayis University, Faculty of Medicine (Samsun, Turkey) between June 2008 and December 2021. All patients had histopathologic confirmation of sPTC (≤10 mm) and underwent regular follow-up for at least 36 months. The tumors had a mean size of 5 mm (0.1-10 mm) and were multifocal in 53.7% of patients. Capsular invasion was observed in 9% of patients. Vascular invasion, lymphatic invasion, and extrathyroidal invasion were present in 2%, 5.5%, and 0.8% of patients, respectively. Metastatic cervical lymph nodes were observed in 9.4% of patients. On multivariate logistic regression analysis, tumor size (odds ratio [OR] 1.380, 95% confidence interval [CI] 1.106-1.722, p = 0.004) and sex (OR 4.233, 95% CI 1.355-13.226, p = 0.013) were the main predictive factors influencing lymph node metastasis. Tumors > 5 mm, compared with tumors ≤ 5 mm, had higher rates of multifocality (p = 0.009), parenchymal invasion (p = 0.008), calcifications (p = 0.001), microscopic lymphatic invasion (p = 0.002), and presence of metastatic lymph nodes (p < 0.001). The findings of this study highlight important factors to consider in making decisions about prophylactic central compartment neck dissection in patients with sPTCs, particularly those with clinically node-negative tumors.

Postoperative morbidity after simultaneous versus staged resection of synchronous colorectal liver metastases: Impact of hepatic tumor burden

BackgroundWe sought to characterize the risk of postoperative complications relative to the surgical approach and overall synchronous colorectal liver metastases tumor burden score. MethodsPatients with synchronous colorectal liver metastases who underwent curative-intent resection between 2000 and 2020 were identified from an international multi-institutional database. Propensity score matching was employed to control for heterogeneity between the 2 groups. A virtual twins analysis was performed to identify potential subgroups of patients who might benefit more from staged versus simultaneous resection. ResultsAmong 976 patients who underwent liver resection for synchronous colorectal liver metastases, 589 patients (60.3%) had a staged approach, whereas 387 (39.7%) patients underwent simultaneous resection of the primary tumor and synchronous colorectal liver metastases. After propensity score matching, 295 patients who underwent each surgical approach were analyzed. Overall, the incidence of postoperative complications was 34.1% (n = 201). Among patients with high tumor burden scores, the surgical approach was associated with a higher incidence of postoperative complications; in contrast, among patients with low or medium tumor burden scores, the likelihood of complications did not differ based on the surgical approach. Virtual twins analysis demonstrated that preoperative tumor burden score was important to identify which subgroup of patients benefited most from staged versus simultaneous resection. Simultaneous resection was associated with better outcomes among patients with a tumor burden score <9 and a node-negative right-sided primary tumor; in contrast, staged resection was associated with better outcomes among patients with node-positive left-sided primary tumors and higher tumor burden score. ConclusionAmong patients with high tumor burden scores, simultaneous resection of the primary tumor and liver metastases was associated with an increased incidence of postoperative complications.

Conditional survival analysis of patients with resected non–small cell lung cancer

BackgroundConditional survival (CS) analyses provide an estimate of survival accounting for years already survived after treatment. We aim to evaluate the difference between actuarial and conditional survival in patients following lung resection for non–small cell lung cancer (NSCLC). In addition, CS analyses are used to examine whether prognosticators of survival change over time following surgery. MethodsPatients who underwent anatomic lung resection at a single institution for pathologic stage I-IIIA NSCLC between 2010 and 2021 were identified; those who underwent wedge resection for node-negative tumors ≤2 cm were also included. CS estimates were calculated as the probability of remaining disease-free after x years of nonrecurrence (CSx). Kaplan–Meier, log-rank, and Cox proportional hazard methods for examining CS were used for subgroup comparisons and assessing associations with baseline covariates. ResultsOverall, 863 patients met the study inclusion criteria, with a median follow-up of 44.1 months. Conditional overall survival (OS) and disease-free survival (DFS) were greater than actuarial rates at all time points after surgery. At the time of resection, male sex (hazard ratio [HR], 1.33; 95% confidence interval [CI], 1.03 to 1.72; P = .032), tumor size >3 cm (HR, 1.17; 95% CI, 1.11-1.23; P < .001), node positivity (HR, 3.31; 95% CI, 2.52-4.33; P < .001), and American Joint Committee on Cancer stage (P < .001) were associated with DFS. However, if a patient lived 3 years without recurrence (CS3), these factors were no longer prognostic of DFS. ConclusionsConditional survival analyses provide dynamic assessments of OS and DFS after NSCLC resection. After 3 years without recurrence, certain characteristics associated with DFS at the time of surgery no longer prognosticate recurrence.

Pattern and time point of relapse in locally advanced esophagogastric adenocarcinoma after multimodal treatment: implications for a useful structured follow-up

PurposeDespite improvements in multimodal treatment of locally advanced esophagogastric adenocarcinoma, the majority of patients still relapses. The impact of structured follow-up for early detection of recurrence is unclear and controversially discussed.MethodsPatients with locally advanced esophagogastric adenocarcinoma having received neoadjuvant/perioperative chemotherapy followed by tumor resection between 2009 and 2021, underwent a structured follow-up including three-monthly imaging during the first 2 years, followed by semiannual and annual examinations in year 3–4 and 5, respectively. Clinical outcome including pattern and time point of relapse was analyzed.ResultsTwo hundred fifty-seven patients were included in this analysis. In 50.2% (n = 129) of patients, recurrent disease was diagnosed, with the majority (94.6%) relapsing within the first 2 years. The most common site of relapse were lymph node metastases followed by peritoneal carcinomatosis and hepatic and pulmonary metastases. 52.7% of patients presented with symptoms at the time of relapse. Cumulative risk and time point of relapse differed significantly between patient with a node-positive tumor (ypN+) after neoadjuvant treatment (high-risk group) and patients with node-negative primary tumor (ypN0) (low-risk group). High-risk patients had a significantly inferior disease-free survival (DFS) and overall survival (OS) with 11.1 and 29.0 months, respectively, whereas median DFS and OS were not reached for the low-risk group.ConclusionsThe risk of relapse differs significantly between high- and low-risk patients. Only a part of relapses is associated with clinical symptoms. An individualized follow-up strategy is recommended for high- and low-risk patients considering the individual risk of relapse.

Radical Cystectomy in the Treatment of Invasive Bladder Cancer: Long-Term Results in 1,054 Patients.

To evaluate our long-term experience with patients treated uniformly with radical cystectomy and pelvic lymph node dissection for invasive bladder cancer and to describe the association of the primary bladder tumor stage and regional lymph node status with clinical outcomes. All patients undergoing radical cystectomy with bilateral pelvic iliac lymphadenectomy, with the intent to cure, for transitional-cell carcinoma of the bladder between July 1971 and December 1997, with or without adjuvant radiation or chemotherapy, were evaluated. The clinical course, pathologic characteristics, and long-term clinical outcomes were evaluated in this group of patients. A total of 1,054 patients (843 men [80%] and 211 women) with a median age of 66 years (range, 22 to 93 years) were uniformly treated. Median follow-up was 10.2 years (range, 0 to 28 years). There were 27 (2.5%) perioperative deaths, with a total of 292 (28%) early complications. Overall recurrence-free survival at 5 and 10 years for the entire cohort was 68% and 66%, respectively. The 5- and 10-year recurrence-free survival for patients with organ-confined, lymph node-negative tumors was 92% and 86% for P0 disease, 91% and 89% for Pis, 79% and 74% for Pa, and 83% and 78% for P1 tumors, respectively. Patients with muscle invasive (P2 and P3a), lymph node-negative tumors had 89% and 87% and 78% and 76% 5- and 10-year recurrence-free survival, respectively. Patients with nonorgan-confined (P3b, P4), lymph node-negative tumors demonstrated a significantly higher probability of recurrence compared with those with organ-confined bladder cancers (P < .001). The 5- and 10-year recurrence-free survival for P3b tumors was 62% and 61%, and for P4 tumors was 50% and 45% , respectively. A total of 246 patients (24%) had lymph node tumor involvement. The 5- and 10-year recurrence-free survival for these patients was 35%, and 34%, respectively, which was significantly lower than for patients without lymph node involvement (P < .001). Patients could also be stratified by the number of lymph nodes involved and by the extent of the primary bladder tumor (p stage). Patients with fewer than five positive lymph nodes, and whose p stage was organ-confined had significantly improved survival rates. Bladder cancer recurred in 311 patients (30%) . The median time to recurrence among those patients in whom the cancer recurred was 12 months (range, 0.04 to 11.1 years). In 234 patients (22%) there was a distant recurrence, and in 77 patients (7%) there was a local (pelvic) recurrence. These data from a large group of patients support the aggressive surgical management of invasive bladder cancer. Excellent long-term survival can be achieved with a low incidence of pelvic recurrence.

Intratumor heterogeneity in colorectal cancer: Distribution of tumor suppressor gene variants with regard to patient lymph node status.

Intratumor heterogeneity (ITH) results from accumulation of somatic mutations in the fractions of successive cancer cell generations. We aimed to use deep sequencing to investigate ITH in colorectal tumors with particular emphasis on variants in oncogenes (ONC) and tumor suppressor genes (TSG). Samples were collected from 16 patients with colorectal cancer and negative or positive lymph node status (n = 8 each). We deep-sequenced a panel of 56 cancer-related genes in the central and peripheral locations of T3 size primary tumors and healthy mucosa. The central region of T3 tumors has a different frequency profile and composition of genetic variants. This mutation profile is capable of independently discriminating patients with different lymph node status (p = 0.028) in the central region. We noted an increasing number of mutations outside of the central region of the tumor and a higher number of mutations in tumors from node-positive patients. Unexpectedly, in the healthy mucosa, we identified somatic mutations with variant allele frequencies, characteristic not only of heterozygotes and homozygotes but also of other discrete peaks (e.g., around 10%, 20%), suggestive of clonal expansion of certain mutant alleles. We found differences in the distribution of variant allele frequencies in TSGs when comparing node-negative and node-positive tumors (p = 0.029), as well as central and peripheral regions (p = 0.00399). TSGs may play an important role in the escape of the tumor toward metastatic colonization.

O096 Expression of MLN70 in breast cancer and the connection with skeletal metastasis

Abstract Introduction MLN70 ([metastatic lymph node gene 70 protein], also known as S100A11 [S100 Calcium-Binding Protein A11] or Calgizzarin), a nucleic and cytosolic protein suspected to have a role in regulation of cellular invasion, migration and tubulin polymerisation in cancer cells and has been implicated in cancer progression. The present study explored how MLN70 might have a value in the clinical outcome of the patients. Methods Expression of MLN70 transcripts was quantified in a clinical cohort of breast cancer and was evaluated against the clinical, pathological, hormonal receptor status and clinical outcome of the patients. Results Breast tumour tissues had higher levels of MLN70 than normal tissues and high levels of MLN70 linked to a shorter overall survival of the patients. MLN70 had a significant correlation with three members of the ERBB family including ERBB1 (EGFR), Her2 (ERBB2) and ERBB4. There were no significant different between node positive and node negative tumours (p=0.237). The most striking finding was that MLN70 showed a significant predictive value in identifying patients who subsequently developed skeletal metastasis (RUC=0.793, p&amp;lt;0.0001 by ROC analysis) and high levels of MLN70 was associated with skeletal metastases (p=0.019, Hazard Ratio 10.93 by regression analysis). Furthermore, multivariate analyses using both linear and regression models indicated MLN70 as being an independent factor for bone metastasis (p=0.016) amongst clinical, pathological and hormone receptor status. Conclusion The present study reveals MLN70 as a significant and independent predictive factor for skeletal metastasis of patients with breast cancer and a prospective target in this cancer type.

O075 Pausing NHSBSP during COVID-19 did not increase advanced cancers and may have avoided overdiagnosis

Abstract Introduction We ascertained the impact of the paused NHS breast cancer screening programme (NHSBSP) during COVID-19 on number and presentation of breast cancer patients. Methods We analysed, breast cancer patients diagnosed across 2 large London NHS trust hospitals in sets: the referral source and numbers in all patients from 2019 to 2021 (n=3,353), and patient/tumour characteristics and treatments received during 6 selected months in 2019 and 2020 (n=318). We analysed proportions using chi-square test. Results Overall, there were 31% fewer patients in 2020 compared with 2019 (1281 vs 886, p=0.002). However, there was no corresponding increase in the number of patients during 2021 (n=1186). The reduction was mainly due to fewer referrals from NHSBSP rather than from GPs (53% reduction vs 13%, p&amp;lt;0.00001). In 2020 vs 2019, there were fewer grade 1 (35 vs 9) and node negative tumours (143 vs 72), without a corresponding increase in grade 2 or 3 (159 vs 104), or node positive cases (54 vs 49); also fewer T1 cases (84 to 37) without a corresponding increase in &amp;gt;T1 cases (113 vs 84); reduced breast conservations (111 vs 71) and negative sentinel nodes (114 vs 69), without increase in mastectomies (35 vs 25) or axillary clearances (32 vs 27). There were no receptor status changes. Conclusion The COVID-19 pause in NHSBSP avoided diagnosis of good prognosis cancers without rapid increase in worse prognosis cancers or more extensive surgery, suggesting that it may have simply avoided overdiagnosis.

O002 Expression of MLN64 (lymph node metastasis 64) gene transcript in clinical gastric cancer and relationship with the ERBB4

Abstract Introduction MLN64 (Lymph Node Metastasis 64, or STARD3 (StAR Related Lipid Transfer Domain Containing 3)) has a role in the progression of certain cancers including breast and prostate cancers and connected to the pattern of ERBB2 (Her2). The present study explored the expression of MLN64 in clinical gastric cancer in connection with the ERBB family. Methods A gastric cancer cohort (n=322) was tested for the expression profile of MLN64 along with the ERBB family members. Comparisons were made between clinical, pathological subgroups and the clinical outcome together with ERBB expression status. Results Gastric tumours expressed significantly raised levels of MLN64 than normal tissues (p=0.0012) and showed a stepwise increase with increased tumour grade and TNM staging. However, there was no significant difference between node negative and node positive tumours. MLN64 alone had a weak value in evaluating the overall (OS) and disease free (DFS) survival. Amongst the four ERBB family members, MLN64 had a significant correlation with ERBB4 (Her4) (p=0.004). Stratification of patients by ERBB4 expression status indicates that in patients with low ERBB4 tumours, MLN64 presents a significant factor in assessing both disease free (DFS) p=0.027) and overall survival (OS) (p=0.048). Similarly, MLN64 expression identified a subpopulation of node positive patients with a most adverse clinical outcome (p=0.009 for DFS and p=0.048 for OS). Conclusion MLN64 expression is an indicator for the disease progression and clinical outcome in gastric cancer. Together with the expression pattern of ERBB4, it makes a prognostic factor for the patients.

Contrast-enhanced ultrasound-guided sentinel lymph node biopsy in early-stage breast cancer: a prospective cohort study

ObjectiveThis study evaluated the identification efficiency of contrast-enhanced ultrasound (CEUS) for sentinel lymph nodes (SLN) to accurately represent the axillary node status in early-stage breast cancer.MethodIn total, 109 consecutive consenting patients with clinically node-negative and T1-2 breast cancer were included in this study. All patients received CEUS to identify SLN before surgery, and a guidewire was deployed to locate SLN in those who were successfully explored by CEUS. The patients underwent sentinel lymph node biopsy (SLNB), and the blue dye was used to trace SLN during the surgery. The decision to perform axillary lymph node dissection (ALND) depended on the intraoperative pathological identification of SLN by CEUS (CE-SLN). The concordance rate of pathological status between CE-SLN and dyed SLN was calculated.ResultThe CEUS detection rate was 96.3%; CE-SLN failed in 4 patients. Among the remaining 105 successful identifications, 18 were CE-SLN positive by intraoperative frozen section, and one with CE-SLN micrometastasis was diagnosed by paraffin section. No additional lymph node metastases were found in CE-SLN-negative patients. The concordance rate of pathological status between CE-SLN and dyed SLN was 100%.ConclusionCEUS can accurately represent the status of axillary lymph nodes in patients with clinically node-negative and small tumor burden breast cancer.Graphical

Abstract 3387: ctDNA dynamics in early stage node negative lung cancers

Abstract Introduction: Patients with early-stage lung cancers have a high risk of relapse and death even after curative surgery. Detection of circulating tumour DNA (ctDNA) in plasma perioperatively is associated with shorter recurrence free survival (RFS). ctDNA-Lung-Detect is an investigator-initiated prospective study of ctDNA detection and association with RFS in patients with early stage non-small cell lung cancer (NSCLC). Methods: Patients with clinically staged T&amp;lt;4cm N0 NSCLC planned for surgical resection at the Princess Margaret/University Health Network underwent ctDNA assessment before and after surgery (~1 month and 1 year). ctDNA minimal residual disease (MRD) was detected using the highly sensitive and specific tumor-informed Residual Disease and Recurrence (RaDaR®, Inivata, Cambridge, UK) assay, which can track up to 48 tumor-specific variants in plasma. Results: Since August 2021, 64 eligible patients were enrolled (Table 1). One had isolated metastasis from a remote non-lung primary and subsequently excluded; another had their preoperative sample missed but was included. Preoperative ctDNA was detected in 15/62 (23.8%) patients and 1/63 (1.6%) post-operatively at the 1-month landmark timepoint (occult N2 disease found at surgery). All but one (93.3%) had ctDNA clearance with surgical resection. Two patients have recurred radiographically and in plasma at 1 year post-operatively, 1/15 with preoperative ctDNA detected (6.7%) and 1/47 without preoperative ctDNA detected (2.1%). Patients with higher T stage, tumor size, squamous histology, and without actionable driver alterations were more likely to have ctDNA detected at any timepoint. Conclusions: In patients with early stage NSCLC (small node negative tumors), 24% have detectable ctDNA pre-operatively. Surgical resection led to ctDNA clearance in 93% of cases. Our results support ongoing testing beyond the initial MRD landmark. Assessment of the impact on RFS post resection is ongoing. Citation Format: Jamie Feng, Tom Waddell, Kazuhiro Yasufuku, Andrew Pierre, Shaf Keshavjee, Jonathan Yeung, Marcelo Cypel, Laura Donahoe, Elliot Wakeam, Marc de Perrot, Jennifer Law, Alexandra Salvarrey, Lisa W. Le, Jennifer Lister, Michael Cabanero, Ming Tsao, Christodoulos Pipinikas, Karen Howarth, Natasha Leighl. ctDNA dynamics in early stage node negative lung cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3387.