High Risk Of Early Relapse Research Articles

Prognostic Value of CSF IL-10 at Early Assessment of Induction Chemotherapy in Primary CNS Lymphomas: A LOC Network Study.

Despite a high response rate at the first evaluation during induction chemotherapy, the risk of early relapse remains high and unpredictable in primary CNS lymphomas (PCSNLs). We aimed to assess the prognostic value of early IL-10 levels in CSF (e-IL-10) after 2 months of induction chemotherapy. We retrospectively selected from the LOC (Lymphomes Oculo-Cérébraux) network database patients with PCSNLs who had complete or partial response at the 2-month evaluation of a high-dose methotrexate-based first-line chemotherapy for whom e-IL-10 was available. Thirty patients (median age: 62 years, brain involvement in 30/30, CSF involvement in 10/30, median baseline CSF IL-10: 27.5 pg/mL) met the selection criteria. e-IL-10 was undetectable in 22 patients and detectable in 8 patients. At the end of induction treatment, 7 of 8 and 4 of 22 of the patients with detectable and undetectable e-IL-10 had experienced progressive disease, respectively (p = 0.001, OR: 26.8, 95% CI 2-1,478). The median progression-free survival times were 5.8 months (95% CI 2.8-8.8) and 28.7 months (95% CI 13.4-43.9) in the groups with detectable and undetectable e-IL-10, respectively (p < 0.001). Our results suggest that despite an objective response, the persistence of detectable e-IL-10 is associated with a high risk of early relapse in PCNSL. A closer follow-up of such patients is warranted.

A randomized, multicenter, open-label, phase III trial comparing anthracyclines followed by taxane versus anthracyclines followed by taxane plus carboplatin as (neo) adjuvant therapy in patients with early triple-negative breast cancer: Korean Cancer Study Group BR 15-1 PEARLY trial.

LBA502 Background: Triple-negative breast cancer (TNBC) is known for its high risk of early relapse and poor prognosis. Platinum agents have shown to increase pathological complete response (pCR) rates when added to neoadjuvant chemotherapy for TNBC. However, evidence regarding the survival benefit of platinum in this setting remains inconclusive. The PEARLY trial is a multicenter, randomized, open-label, phase 3 study designed to assess the efficacy and safety of carboplatin in combination with anthracycline/taxane therapy compared to standard anthracycline/taxane alone as either neoadjuvant or adjuvant treatment in early-stage TNBC. Methods: Patients with stage II or III TNBC were randomly assigned to either the carboplatin arm or the standard therapy arm, stratified by nodal status, institution, treatment setting (neoadjuvant vs adjuvant), and germline BRCA status. The standard therapy involved doxorubicin and cyclophosphamide (AC) followed by taxane treatment. The experimental arm included carboplatin in addition to taxane following AC. The primary endpoint was event-free survival (EFS), defined as disease progression or inoperable status for neoadjuvant therapy group, local or distant recurrence, occurrence of a second primary cancer, or death from any cause, while secondary endpoints encompassed overall survival (OS), invasive disease-free survival (IDFS), distant recurrence-free survival (DRFS), pCR rate, and safety. With a planned enrollment of 878 patients, the trial aimed for 80% power to detect a hazard ratio of 0.70 for EFS at a two-sided alpha level of 0.05, anticipating 248 EFS events over a 5-year follow-up period. Results: Between Jan 2016 and Jun 2020, 868 patients across 22 institutions in South Korea were enrolled. At a median follow-up of 51.1 months, carboplatin significantly improved EFS compared to the control arm (hazard ratio [HR], 0.68; 95% confidence interval [CI]: 0.50 to 0.93; p=0.017). The 5-year EFS rates were increased from 74.4% to 81.9%, demonstrating a 7.5% difference. Subgroup analysis showed consistent benefits across various patient categories. Secondary endpoints like IDFS and DRFS also favored carboplatin arm. OS data were immature, a total of 43 patients (10.2%) in the carboplatin arm and 57 patients (13.1%) in the control arm died (HR 0.66; 95% CI: 0.42 to 1.01). Grade ≥3 treatment-related adverse event rates were 74.6% (1 death due to infection) in the carboplatin arm and 56.7% (2 deaths due to infection and suicide) in the control arm. Conclusions: The addition of carboplatin to standard anthracycline followed by taxane therapy significantly improved EFS in patients with early-stage TNBC. The safety profile was consistent with the known expectations for each regimen. Clinical trial information: NCT02441933 .

Abstract PO5-19-07: A Single Arm Phase 2 Study of Peri-Operative Immune Checkpoint Inhibition and Cryoablation in Women With Hormone Receptor-Negative, HER2-Negative Early Stage/Resectable Breast Cancer

Abstract Background: Triple negative breast cancer (TNBC) is a biologically distinct subtype with a high risk of early relapse. Patients not achieving a pathological complete response (pCR) after neoadjuvant chemotherapy (NAC) have a 3-year event free survival (EFS) of &amp;lt; 60%. Approximately 1/3 of patients receiving NAC with pembrolizumab-mediated immune therapy will not achieve a pCR and of those, approximately 1/3 will experience a recurrence within 3 years. Physical disruption of tumors with local strategies such as cryoablation (cryo) induces inflammation and releases antigens that can activate tumor-specific immune responses. The combination of cryo with immune checkpoint inhibition (ICI) has been shown to induce tumor regression and prevented tumor re-challenge in pre-clinical models. Clinical studies have also demonstrated that the combination of pre-operative cryo with ICI is safe in women with operable, early-stage breast cancer and generates intra-tumoral and systemic immune responses (NCT01502592, NCT02833233). This multi-center, single arm, phase 2 study is currently evaluating the impact of cryo with standard-of-care pembrolizumab (pembro) in women with residual TNBC after taxane-based NAC, a group at high risk of early relapse (NCT03546686). Methods: Eligible women are ≥18y, with ER &amp;lt; 10%, PR &amp;lt; 10%, HER2 negative (per ASCO/CAP definition), ≥ 1.0 cm, residual operable disease after taxane-based NAC. Pts undergo percutaneous, image-guided cryo with concurrent research core biopsy 7-10 days prior to surgery and receive peri-operative pembro per standard-of-care. Adjuvant capecitabine or olaparib is recommended for all patients per local standard-of-care. Patients are stratified by NAC platinum administration, NAC anthracycline administration, and clinical nodal status (positive versus negative). The primary endpoint is 3-year Event Free Survival (EFS). Secondary endpoints include Invasive Disease-Free Survival (IDFS), Distant Disease-Free Survival (DDFS), overall survival (OS) and safety. Exploratory correlative studies will be performed on tumor and serum to characterize the immunologic impact of the intervention and to explore predictors of efficacy and toxicity. Funding sources: Conquer Cancer Foundation, Breast Cancer Research Foundation, Boston Scientific Citation Format: Heather McArthur, Elizabeth Comen, Yolanda Bryce, Stephen Solomon, Sangeetha Reddy, Isaac Chan, Baṣak Dogan, Dawn Klemow, Nisha Unni, Jorge Henrique Santos Leal, Cristal Martinez, Reva Basho, Dorothy Park, Philomena McAndrew, Brigid Larkin, David Page, William Mills, Staci Mellinger, Nicole Fredrich, Nicole Moxon, Lynette Currie, Meredith Carter, Melissa Ramos, Stephanie Rice, Sujata Patil, Margaret Gatti-Mays, Larry Norton. A Single Arm Phase 2 Study of Peri-Operative Immune Checkpoint Inhibition and Cryoablation in Women With Hormone Receptor-Negative, HER2-Negative Early Stage/Resectable Breast Cancer [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 PO5-19-07.

Gene expression prognostic of early relapse risk in low-risk B-cell acute lymphoblastic leukaemia in children.

ETV6::RUNX1 is the most common fusion gene in childhood acute lymphoblastic leukaemia (ALL) and is associated with favorable outcomes, especially in low-risk children. However, as many as 10% of children relapse within 3 years, and such early relapses have poor survival. Identifying children at risk for early relapse is an important challenge. We interrogated data from 87 children with low-risk ETV6::RUNX1-positive B-cell ALL and with available preserved bone marrow samples (discovery cohort). We profiled somatic point mutations in a panel of 559 genes and genome-wide transcriptome and single-nucleotide variants. We found high TIMD4 expression(>85th-percentile value) at diagnosis was the most important independent prognostic factor of early relapse (hazard ratio [HR]=5.07 [1.76, 14.62]; p=0.03). In an independent validation cohort of low-risk ETV6::RUNX1-positive B-cell ALL (N=68) high TIMD4 expression at diagnosis had an HR=4.78 [1.07, 21.36] (p=0.04) for early relapse. In another validation cohort including 78 children with low-risk ETV6::RUNX1-negative B-cell ALL, high TIMD4 expression at diagnosis had an HR=3.93 [1.31, 11.79] (p=0.01). Our results suggest high TIMD4 expression at diagnosis in low-risk B-cell ALL in children might be associated with high risk for early relapse.

Identification of Clinical-Biological Features of Newly Diagnosed Early Relapse Multiple Myeloma Patients Eligible for Autologous Stem Cell Transplantation

Despite many therapeutics advances, Multiple Myeloma (MM) remains an incurable hematological malignancy with a cohort of patients who relapse early or does not respond to first-line therapy, including autologous stem cell transplantation (ASCT). The proportion of patients with early relapse is stable over time at about 30% and they have a median Overall Survival (OS) less than 3 years. Consequently, clinical and/or biological features that identify patient at high risk for early relapse at diagnosis represent a critical unmet medical need. With the aim of identify possible factors of early relapse (ER), we conducted a retrospective, observational, single center study on a cohort of 74 MM patients who received an upfront ASCT between 2011 and 2021 after a novel agent-based induction at the Hematological and BMT Unit of the University Hospital of Parma (Italy). The primary end point of the study was the assessment of possible predictive markers for ER, defined as progressive disease that occurred within 18 months from the time of ASCT. Clinical, biochemical and cytogenetics features of the cohort of MM patients were evaluated (Table 1). Definitions of response and progression were used according to the International Myeloma Working Group (IMWG) response criteria. All statistical analyses were done by SPSS Statistics. The characteristics of cohorts were summarized using the median value for continuous variates and the frequency for categorical ones. The Pearson chi-square test and Student t-test were used to identify differences between groups for categorical and continuous variables, respectively. Kaplan-Meier Curve with log-rank test were used to analyze survival data. The bivariate logistic analysis was conducted to recognize independent factors predicting ER, subsequently Cox regression analysis was performed to confirm the validity of multivariate analysis for survival data. The cohort characteristics were summarized in table 1. Among the 74 MM patients included in the study, a total of 19 patients (25.5) experienced ER, with mean time to relapse of 15.6 (18.0) months. Univariate statistical analysis identified as possible predictive markers for early relapse at diagnosis: IgA MM (p &amp;lt; 0.05), elevated serum LDH level (p &amp;lt; 0.05), C-CRAB criteria (p &amp;lt; 0.05), high risk cytogenetic aberrations (p &amp;lt; 0.05), stage R-ISS III (p &amp;lt; 0.001) and stage R2-ISS III or IV (p &amp;lt; 0.001). Multivariate statistical analysis confirmed IgA isotype (p &amp;lt; 0.05) and higher stage according to R2-ISS (p &amp;lt; 0.001) as effectively independent predictive risk factors for ER. Time-to-event analysis displayed a mean progression free survival (PFS) from transplant of 24.7 (16.0) months and 32.5 (19.0) months for those with IgA MM and stage R2-ISS III or IV, respectively. In the group of patients with IgA isotype the mean OS from transplant was 49.5 (30.0) months, while the mean OS from diagnosis was 58.0 (35.0) months without statistically significant differences compared to counterpart. In the group of patients with stage R2-ISS III or IV the mean OS from transplant was 48.2 (41.0) months, while the mean OS from diagnosis was 56.5 (49.0) months. Finally, in ER cohort the mean OS from diagnosis was 47.1 (35.0) in comparison with the 75.0 (71.0) months of non-ER cohort. In conclusion, this retrospective study was able to identify the main features of newly diagnosed early relapsed MM patients eligible to ASCT identifying the IgA isotype and the R2-ISS score system as the main predictive prognostic factors for early relapse in this cohort of patients.

Leveraging Deep Neural Networks to Predict Time to Event in Pediatric B-Lymphoblastic Leukemia

Children treated for B-Acute Lymphoblastic Leukemia (ALL) have high rates of recurrence. In order to overcome such challenges, patients require consolidation therapy that ranges from additional chemotherapy to hematopoietic stem cell transplant. Even so, approximately 50% of children with first relapse survive long term, which is important to determine the appropriate consolidation therapies. Currently, the most relevant risk stratification includes age, minimal residual disease (MRD) status seen in bone marrow 28 days post-induction, and cell count at the time of diagnosis. As the body of literature grows, there is a greater need to incorporate molecular data to assist in risk stratification. In recent decades, microRNA (miRNA), which are non-coding RNA that regulate post-transcriptional modification, have been implicated in the pathogenesis of B-ALL. Due to the volume of variables, it is difficult to model such relationships using conventional methods. Thus, the objective was to generate a machine learning model to predict response to induction therapy by leveraging the Therapeutically Applicable Research to Generate Effect Treatment (TARGET) databases. Between January 1, 2004 and January 1, 2011, the TARGET database collected data on over 11,000 patients with ALL up to the age of 31 that included clinical data such as age, gender, cytogenetics, and event-free survival (EFS). An event was defined as induction failure, relapse, progression, second hematologic malignancies, and death. In the expansion phase 2 part of the study, 175 children with B-ALL had in-depth genomic sequencing. Because of the unpredictable downstream effects of dysregulation of miRNA, underlying assumptions of the Cox proportional hazard model may be violated. Machine learning models, such as the DeepSurv model, leverage deep neural networks to analyze survival data. The DeepSurv model has demonstrated superior performance in capturing linear and non-linear relationships between covariates and time-to-event analysis. In total, 171 features including age, MRD status, White Blood Cell (WBC) count at diagnosis, and 168 miRNA counts were included in the model. Random forest (RF) models were utilized to stratify the impact of features that are predictive. We created a 6773-parameter model using 171 features. A 10-fold cross-validation showed a concordance-index of 0.652 (CI: 0.582 - 0.752). Figure 1 shows the observed and predicted normalized EFS using DeepSurv. Notably, it is able to identify early relapse in the bottom L quadrant. Figure 2A shows the decision tree for the RF model that shows features and cut-offs as rules that cluster the EFS times. Figure 2B shows the features that were impactful for the RF decision rules. In this work, we aim to leverage machine learning algorithms and miRNA to identify children who are at high risk for early relapse and can help clinicians to strategize consolidation therapy. We showed a reasonable concordance score that gives us a signal for potential impact. Further research, utilizing larger sample sizes, should serve to externally validate this model. Appropriate clinical application of such models has the potential to improve survival and limit treatment toxicity through a truly personalized approach to the patient and the unique genetic profile of their malignancy.

P14.08.A PROGNOSTIC VALUE OF CSF IL-10 AT THE 2-MONTH ASSESSMENT AFTER THE START OF INDUCTION CHEMOTHERAPY IN PRIMARY CNS LYMPHOMAS. A LOC NETWORK STUDY

Abstract BACKGROUND Despite a high rate of objective response at first evaluation of ongoing high dose methotrexate (hd MTX) based induction chemotherapy, the risk of early relapse remains high and unpredictable in patients suffering from primary CNS lymphomas (PCSNL). Since cerebrospinal fluid (CSF) IL-10 level has been shown prognostic in PCNSL, both before and at the end of the treatment, it is used in routine in some centers. The objective of the present study was to assess the prognostic value of early CSF IL-10 level (e-IL-10), performed 2 months after the beginning of the induction chemotherapy. MATERIAL AND METHODS We retrospectively selected the immunocompetent patients treated at Pitié-Salpêtrière hospital and Institut Curie for a PCNSL diagnosed between January 2019 and July 2022 according to the following criteria : histological diagnosis of diffuse large B-cell lymphoma ; hd MTX-based chemotherapy as induction in first line treatment; complete response (CR) or partial response (PR) according to the IPCG criteria at the 2-month evaluation; availibility of dosage of e-IL-10. CSF IL-10 was classified as detectable (≥2.5 pg/ml) or undetectable (&amp;lt;2.5 pg/ml) RESULTS Thirty patients (median age 63 years, median KPS 70, 17 men) met the selection criteria. At initial diagnosis, all patients presented with brain lymphoma, associated with CSF (N=10) and/or intraocular involvement (N=2). Before treatment, 22 of them had a dosage of CSF IL-10, which was detectable in 21 cases (median 27.5 pg/mL, range 3-1844 pg/mL), with a ratio IL-10/IL-6&amp;gt;1 in 21 cases. At the 2-month evaluation after the beginning of the treatment, 25 patients were in PR and 5 were in CR and e-IL-10 was undetectable in 22 patients and detectable in 8 patients, with the following values: 105, 30, 20, 16, 14, 10, 6, 3 pg/mL . For the patients with detectable e-IL-10, e-IL-10 was superior to initial IL-10 level in 1 case and inferior in 5 cases (no data at baseline for 2 patients) and the ratio CSF e-IL-10/e-IL-6 was superior to 1 in 8/8 cases. At the end of induction treatment, all but one patient (the one with an e-IL-10 value of 3 pg/ml) had experienced progressive disease in the group with detectable e-IL-10 (2 progression in the brain, 5 in the CSF) vs 4/22 patients in the group with undetectable e-IL-10 (p=0.001). The median follow-up was 16 months. Median PFS was 5.8 months in the group with detectable e-IL-10 and 28.6 months in the group with undetectable e-IL-10 (p=0.0001). 1-year OS was 71% in the group with detectable e-IL-10 and 86% in the group with undetectable e-IL-10 (p=0.36). CONCLUSION Our results suggest that detectable CSF IL-10 at 2 months after the start of first line induction chemotherapy in PCNSL is associated with a high risk of early relapse and that closer follow-up of these patients is warranted. Further studies are needed to confirm these results and to assess whether the therapeutic strategy should be adapted accordingly in these cases.

Lenalidomide and Carfilzomib in Relapsed and Refractory T Follicular Helper Lymphomas

Non-Hodgkin T-cell lymphomas represent a heterogeneous group of aggressive haematological malignancies with a high risk of early relapse or resistance to standard treatment protocols. One significant drawback is that chemotherapy protocols were initially designed for B-cell lymphomas, and targeted studies for T-cell lymphomas were only recently developed. Due to the rising incidence of peripheral T cell lymphomas (PTCL) in recent years, there is a need for new therapies to effectively treat these types of malignancies. Incorporating gene expression profile (GEP) studies in the standard diagnostic tests could enable treatments specifically tailored to each patient's needs. In this article we present the case of a patient diagnosed nodal-T follicular helper cell lymphoma, who exhibited early relapse following the standard chemotherapy protocol in our country. After multiple lines of treatment without favorable response, we conducted an off-label treatment combining Lenalidomide (an immunomodulatory drug) and Carfilzomib (a selective irreversible proteasome inhibitor). This therapeutic approach was previously done in other studies, but it involved also the use of Romidepsin, a histone deacetylase inhibitor (HDACi). We did not use Romidepsin in this patient as it is not approved in the European Union for patients with PTCL.

A single-arm phase 2 study of peri-operative immune checkpoint inhibition and cryoablation in women with hormone receptor-negative, HER2-negative, early-stage/resectable breast cancer.

TPS635 Background: Local tumor destruction with cryoablation (cryo) induces inflammation and releases antigens that can activate tumor-specific immune responses. Pre-clinically, cryo with immune checkpoint inhibition (ICI) augmented tumor-specific immune responses and prevented recurrence. Clinically, we established that peri-operative (peri-op) cryo with ICI [ipilimumab (ipi) +/- nivolumab (nivo)] was safe in patients (pts) with operable, early stage breast cancer (ESBC) and generated robust intra-tumoral and systemic immune responses. In this phase 2 study, we evaluate the disease specific impact of peri-op ICI in women with residual triple negative breast cancer (TNBC) after neoadjuvant chemotherapy (NAC), a subset at high risk of early relapse. Methods: Eligible women are ≥18y, with ER &lt;10%, PR &lt;10%, HER2 negative (per ASCO/CAP definition), ≥ 1.0 cm, residual operable disease after taxane-based NAC. As of 2/14/21, 16/80 pts have been enrolled and treated with ipi/nivo/cryo followed by breast surgery and adjuvant nivo. Pts undergo percutaneous, image-guided cryo with concurrent research core biopsy 7-10 days prior to surgery and received ipi (1mg/kg IV) with nivo (240mg IV) 1 to 5 days prior to cryo. After surgery, pts received 3 additional doses of nivo at 240mg IV Q2 weeks. To reflect the US FDA approval of curative-intent pembrolizumab (pembro) in 2021, the protocol was recently amended to allow standard-of-care pembro as an alternative ICI option. Adjuvant capecitabine or olaparib is recommended for all patients per local standard-of-care. Patients will be stratified by NAC platinum administration, NAC anthracycline administration, and clinical nodal status (positive versus negative). The primary endpoint is 3-year Event Free Survival (EFS). Secondary endpoints include Invasive Disease-Free Survival (IDFS), Distant Disease-Free Survival (DDFS), overall survival (OS) and safety. Exploratory correlative studies will be performed on tumor and serum to characterize the immunologic impact of the intervention and to explore predictors of efficacy and toxicity. Clinical trial information: NCT03546686 .

Detection of circulating tumor DNA following neoadjuvant chemotherapy and surgery to anticipate early relapse in ER positive and HER2 negative breast cancer: Analysis from the PENELOPE-B trial.

502 Background: The PENELOPE-B phase III trial investigated the addition of one year of palbociclib to endocrine therapy (ET), in patients with hormone receptor positive HER2 negative breast cancer with residual invasive disease after neoadjuvant chemotherapy. Prior research has demonstrated that detection of circulating tumor DNA (ctDNA) in the adjuvant setting is associated with a high risk of disease relapse. We assessed the potential of ctDNA analysis to predict future clinical relapse for patients enrolled in the PENELOPE-B trial. Methods: Patients who were endocrine naïve at the time of study entry were selected for ctDNA analysis. Plasma samples were collected at baseline (after completion of neoadjuvant chemotherapy and surgery), prior to cycle 7 (approximately 6 months into ET +- palbociclib), end of treatment (EOT), and progressive disease. A tumor sample was subjected to exome sequencing, and up to 50 tumor somatic mutations were tracked in plasma using error-corrected sequencing combined with a proprietary algorithm for ctDNA detection (RaDaR assay). Detection of ctDNA was associated with invasive disease-free survival (iDFS) and distant metastasis-free survival using Cox proportional hazard models. Results: Of 1250 patients enrolled in PENELOPE-B, 129 were endocrine naïve at trial entry, and 78 had a baseline ctDNA sample analyzed. The ctDNA analysis group was representative of the overall endocrine naïve group, with median follow-up of 42.9 months. Seven patients had baseline ctDNA detected, with detection strongly associated with iDFS (HR 8.8, 95% CI 3.3-23.4, p &lt; 0.0001). Detection of ctDNA at cycle 7 (4 patients) was also strongly associated with iDFS (HR 25.5, 95% CI 6.5-99.6, p &lt; 0.0001). Of the 7 patients with baseline ctDNA detection, 2 had undetectable ctDNA at cycle 7 and remained progression free at 30 months, although one later relapsed; the 3 patients with detectable ctDNA at cycle 7 all relapsed within 25 months. Of the 12 patients with a distant relapse within 24 months, only 4 had ctDNA detected at baseline and 3 first at cycle 7/EOT. Of the 8 patients with distant relapse after 24 months, 2 had ctDNA detected at baseline and none first at cycle 7/EOT. Conclusions: Detection of ctDNA following neoadjuvant chemotherapy, and surgery, is associated with a very high risk of early relapse suggesting limited efficacy of adjuvant ET. Clinical imaging and studies of experimental therapy are warranted in this patient population. Testing ctDNA after recent neoadjuvant chemotherapy in luminal-A like breast cancer has relatively low ‘sensitivity’ for predicting future relapse, in particular for later relapses, in part suggesting that response to neoadjuvant chemotherapy may reduce ctDNA detection. Clinical trial information: NCT01864746 .

Abstract 1318: Potential mechanism of re-dissemination from lung metastases to tertiary sites in breast carcinoma: Tumor microenvironment of metastasis doorways and related pro-metastatic tumor phenotypes

Abstract Background: The five-year relative survival rate of female breast cancer patients with distant metastases is only 29%, compared to 99% for localized disease. Among all subtypes, triple negative breast cancer (TNBC) has the poorest outcome due to a high risk of early relapse with visceral organ metastases, and a lack of targeted therapies. Targeting metastatic burden could improve patient survival. Recent mouse and human genomic profiling studies show that metastasis is a complex and multidirectional process. Cancer cells can re-disseminate from one metastasis to tertiary sites. But the mechanism of re-dissemination is unknown. Breast cancer cells disseminate from primary tumors via Tumor MicroEnvironment of Metastasis (TMEM) doorways, composed of three cells: a tumor cell, a perivascular macrophage, and an endothelial cell. The direct and stable interaction of these cells cause transient and local vascular opening through which metastasis-competent tumor cells co-expressing invasive, stem, and dormant phenotypes that preferentially reside around TMEM doorways disseminate to distant sites. We hypothesize that TMEM doorways also form in lung metastases, enabling cancer cell re-dissemination to tertiary sites, which increases overall cancer burden and risk of death. Methods: We used MDA-MB-231 and MDA-MB-468 human TNBC cells to generate tumors in the 4th mammary fat pad of 6-8 weeks old NOD/SCID mice. Primary tumors were resected when 5-6 mm and fixed with 10% formalin. When lung metastases were visible via micro-Computed Tomography (microCT) fluorescent dextran was injected intravascularly, and lungs collected and fixed with 10% formalin. Triple immunohistochemistry was used to visualize TMEM doorways. To test TMEM doorway-mediated vascular opening, sequential slides were stained for extravascular dextran. Cells co-expressing stem (SOX9), invasive (MenaINV), and dormant (NR2F1) markers were visualized by immunofluorescent staining. The density of TMEM doorways, CSCs, invasive, and dormant cells was determined by automated image analysis. Results: We demonstrated the presence and activity of TMEM doorways in lung metastases. Within lung metastases, we also documented the presence of cancer cells with a pro-metastatic phenotype indicated by their co-expression of invasive (MenaINV), stemness (SOX9), and dormancy (NR2F1) markers. We will report how the expression of pro-metastatic markers relates to TMEM doorway niches. Conclusion: We documented functional TMEM doorways in lung metastases of TNBC, which could explain the occurrence of an early overall metastatic burden in patients with TNBC. Thus, targeting TMEM doorways after the removal of the primary tumor in patients with TNBC could block cancer cell re-dissemination, decrease metastases, and improve survival. Citation Format: Burcu Karadal-Ferrena, Camille L. Duran, Madeline Friedman-DeLuca, Nicole Barth, Prachiben Patel, John S. Condeelis, David Entenberg, Maja H. Oktay. Potential mechanism of re-dissemination from lung metastases to tertiary sites in breast carcinoma: Tumor microenvironment of metastasis doorways and related pro-metastatic tumor phenotypes [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 1318.

Prognostic nomogram for multiple myeloma early relapse after autologous stem cell transplant in the novel agent era.

The present study intended to establish a predictive nomogram for early relapse (ER) (<12 months) after autologous stem cell transplantation (ASCT) in the novel drug era for multiple myeloma (MM). The nomogram was designed and constructed to a retrospective clinical data of newly diagnosed MM patients received novel agent induction therapy and subsequent ASCT at three centers in China from July 2007 to December 2018. The retrospective study was conducted among 294 patients in the training cohort and 126 in the validation cohort. The nomogram's predictive accuracy was evaluated by the concordance index, calibration curve and decision clinical curve. The study cohort included 420 newly diagnosed MM patients, and 100 (23.8%) were identified as having ER, including 74 in the training cohort and 26 in the validation cohort. According to the result of multivariate regression in the training cohort, the prognostic variables included in the nomogram were high-risk cytogenetics, LDH > UNL, and response less than very good partial response (VGPR) after ASCT. The calibration curve showed good fitness between the nomogram predictions and the actual observations and the nomogram was further validated by a clinical decision curve. The nomogram's C-index achieved 0.75 (95% CI, 0.70-0.80), which was higher than that of the Revised International Staging System (R-ISS) (0.62), ISS (0.59), and Durie-Salmon (DS) staging system (0.52). The discrimination ability of the nomogram in the validation cohort was superior to that of the other staging systems (C-index: 0.73 vs. R-ISS (0.54), ISS (0.55), and DS staging system (0.53)). DCA showed the prediction nomogram adds much more clinical utility. Different scores of the nomogram draw a distinction of OS. The present nomogram could serve as a feasible and accurate prediction of ER in novel drug induction transplantation-eligible MM patients, which could help modify the post-ASCT strategy for patients at high risk of ER.

Abstract OT1-19-01: A Single Arm Phase 2 Study of Peri-Operative Checkpoint-Mediated Immune Therapy and Cryoablation in Women with Hormone Receptor-Negative, HER2-Negative Early Stage/Resectable Breast Cancer

Abstract Background: Local tumor destruction with cryoablation (cryo) induces inflammation and releases antigens that can activate tumor-specific immune responses. Pre-clinically, cryo with immune checkpoint inhibition (ICI)-augmented tumor-specific immune responses and prevented recurrence. Clinically, we established that peri-operative (peri-op) cryo with ipilimumab (ipi) +/- nivolumab (nivo) was not only safe in patients (pts) with operable, early stage breast cancer (ESBC) but also generated robust intra-tumoral and systemic immune responses. In this phase 2 study, we evaluate the disease specific impact of peri-op ICI in women with residual triple negative breast cancer (TNBC) after neoadjuvant chemotherapy (NAC), a subset at high risk of early relapse. Methods: Eligible pts are ≥18y, with ER &amp;lt; 10%, PR &amp;lt; 10%, HER2 negative (per ASCO/CAP definition), ≥ 1.0 cm, residual operable disease after taxane-based NAC. Approximately 80 pts will be enrolled and treated with ipi/nivo/cryo followed by breast surgery and adjuvant nivo across multiple institutions. Pts undergo percutaneous, image-guided cryo with concurrent research core biopsy 7-10 days prior to surgery and will receive ipi (1mg/kg IV) with nivo (240mg IV) 1 to 5 days prior to cryo. After surgery, pts will receive 3 additional doses of nivo at 240mg IV Q2 weeks. Adjuvant capecitabine is recommended for all patients per local standard-of-care. Patients will be stratified by NAC platinum administration, NAC anthracycline administration, and clinical nodal status (positive versus negative). The primary endpoint is 3-year Event Free Survival (EFS). Secondary endpoints include Invasive Disease-Free Survival (IDFS), Distant Disease-Free Survival (DDFS), overall survival (OS) and safety. Exploratory correlative studies will be performed on tumor and serum to characterize the immunologic impact of the intervention and to explore predictors of efficacy and toxicity. Funding sources: Susan G. Komen, ASCO Conquer Cancer Foundation, Breast Cancer Research Foundation, Bristol-Myers Squibb, BTG International Ltd. NCT03546686 Citation Format: Heather McArthur, Elizabeth Comen, Yolanda Bryce, Stephen Solomon, Jorge Henrique Santos Leal, Christina DiLauro Abaya, Cristal Martinez, Reva Basho, Dorothy Park, Philomena McAndrew, Brigid Larkin, William Mills, David B. Page, Staci Mellinger, Nicole Fredrich, Nicole Moxon, Sangeetha Reddy, Meredith Carter, Sujata Patil, Larry Norton. A Single Arm Phase 2 Study of Peri-Operative Checkpoint-Mediated Immune Therapy and Cryoablation in Women with Hormone Receptor-Negative, HER2-Negative Early Stage/Resectable Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT1-19-01.

Risk factors for early relapse in patients with biliary tract cancers who underwent curative resection: An exploratory subgroup analysis of JCOG1202.

541 Background: Relapse after highly invasive surgery for biliary tract cancers (BTCs), especially in the early postoperative period, causes medical, psychological, social, and economic disadvantages to the patients. However, approximately 30% of patients with curatively resected BTCs experience relapse within the first 12 months. JCOG1202 (UMIN000011688) is a randomized phase III trial conducted in patients with resected BTCs showing the benefit of adjuvant S-1 for overall survival. This study aimed to investigate the risk factors for early relapse of resected BTCs in the JCOG1202 cohort. Methods: Of the 440 patients enrolled in the JCOG1202, 217 patients who received surgery alone (arm A) and 207 patients who received adjuvant S-1 (arm B) were eligible and included in this analysis. Early relapse was defined as relapse or death within 12 months after enrollment. Predictive factors for early relapse were assessed using logistic regression analyses. Results: Postoperative early relapse was observed in 59 (27.2%) and 38 (18.4%) of patients in arm A and arm B, respectively. In multivariable logistic regression analysis for the 424 eligible patients, postoperative CA19-9 levels &gt;37 u/ml (odds ratio (OR): 2.790, 95% confidence interval (CI): 1.262-6.170), poorly differentiation (vs. well-differentiated/papillary) (OR: 4.746, 95% CI:1.927-11.688), moderate differentiation (vs. well-differentiated/papillary) (OR: 1.955, 95% CI:1.071-3.567), lymph node metastases &gt; 4 (vs. 0) (OR: 3.991, 95% CI: 1.674-9.514), lymph node metastases 1-3 (vs. 0) (OR: 2.661, 95% CI: 1.471-4.814), and presence of residual tumor (OR: 2.171, 95% CI: 1.070-4.408) were independent risk factors for early relapse. Importantly, adjuvant S-1 chemotherapy significantly reduced early relapse (OR: 0.491, 95% CI: 0.290-0.833). Similar results were observed in arm B. Conclusions: Postoperative CA19-9 level, tumor differentiation, lymph node metastases, and the residual tumor significantly impact early relapse in patients with curatively resected BTCs. Although adjuvant S-1 chemotherapy was effective in reducing early relapse, similar factors tended to be the risk factors in patients receiving adjuvant S-1 chemotherapy. Patients at high risk of early relapse may need more intensive perioperative therapy. Clinical trial information: UMIN000011688 .

Mutations of ATM Confer a Risk of Inferior Survival in Patients with TP53-wild Type Mantle Cell Lymphoma

Background: Despite improved approaches to prognostication in mantle cell lymphoma (MCL), the impact of specific genomic aberrations is not well-described beyond TP53, which is well recognized as a high-risk marker across malignancies and widely assessed at time of diagnosis. However, since outcomes in patients without TP53 aberrations can be highly variable and difficult to predict, additional molecular markers are needed to identify patients who are at high risk for early relapse and inferior OS (Bond et al, Blood Adv 2021). In this study, we used comprehensive whole exome and transcriptome sequencing to genomically assess the prognostic impact of recurrent abnormalities in patients with MCL with and without TP53 aberrations. Methods: The Atlas of Blood Cancer Genomes (ABCG) project is a worldwide effort to systematically profile the genetic alterations and expression changes in all blood cancers. We recruited MCL patients with detailed clinical data available and subjected their tumors to whole exome and transcriptome sequencing. TP53-aberrant cases were identified from the genomic and diagnostic data. Progression-free survival (PFS) and overall survival (OS) were measured from the date of diagnosis until date of progression/relapse or death (PFS) or death (OS) using the Kaplan-Meier method and statistical comparisons by the logrank test. Results: Whole exome and whole transcriptome sequencing was performed successfully for 252 patients with MCL. Consistent with previous descriptions of the disease, median age at diagnosis was 65 years (range: 32-96), and 73% of patients were male. Seventy-five percent of patients had stage IV disease, and MIPI score was high, intermediate, or low in 34%, 34%, and 32% of patients, respectively. Ki67 proliferative index was ≥30% in 48% of patients with available data (n=115). Most patients received commonly used MCL therapies. Of the 185 patients for whom first-line treatment was known, 28% received bendamustine-containing regimens, 42% received cytarabine-containing regimens, and the remaining 30% received other regimens. Twenty-one percent of patients underwent autologous stem cell transplant consolidation as part of first-line therapy. Seventeen percent of patients had blastoid or pleomorphic histology, and 3% had leukemic non-nodal type MCL. Median PFS for the entire cohort was 41 months, and median OS was 138 months. As expected, patients with a confirmed TP53 abnormality (n=39) had inferior median OS compared to TP53-WT patients (n=84; 39 months vs 138 months, p<0.001). Recurrent mutations identified in TP53-aberrant and TP53-WT patients are presented in Figure 1. Among TP53-WT patients, the following genes were mutated in ≥10% of cases: ATM (45%), KMT2D (23%), PTPN13 (13%), NOTCH1 (13%), NSD2 (11%), and SPEN (10%). Incidence of ATM mutations in TP53-aberrant patients was 21% and was less common in patients with TP53 mutations (14%) rather than deletions (30%). Presence of an ATM mutation (median variant allele frequency 43%; range 15-96%) in TP53-WT patients was associated with inferior median PFS (38 months vs 138 months for ATM WT, p=0.023) (Figure 2); median OS was also shorter in patients with ATM mutations (104 vs 138 months, p=0.035). Although the incidence of ATM mutations was lower in TP53-aberrant patients, there was no significant association between ATM mutation and PFS or OS in that subgroup. Conclusions: To our knowledge, this study represents the largest genomic characterization of clinical outcomes in MCL patients. These findings suggest a pathogenic role for ATM mutations in patients with TP53-WT MCL and provide molecular insights into their heterogeneous outcomes. Although ATM mutations have been previously shown to be mutually exclusive with TP53 mutations (Mareckova et al, Leukemia & Lymphoma 2019), to our knowledge this is the first study that shows prognostic differences by ATM mutation status among TP53-WT patients. Our data indicate that ATM mutations are a significant prognostic factor and should be assessed at diagnosis along with TP53. Further clinical investigation of ATM mutations in TP53-WT MCL patients will be important to determine how this molecular marker may inform risk stratification and treatment approaches. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Temporalis muscle thickness predicts early relapse and short survival in primary CNS lymphoma.

Most patients with primary CNS lymphoma (PCNSL) achieve durable remission whereas a minority die in the first year. Sarcopenia is a powerful predictor of mortality in the brain and systemic cancers. Temporalis muscle thickness (TMT) is a validated radiographic measure of sarcopenia. We hypothesized that patients with thin TMT at diagnosis would have early progression and short survival. Two blinded operators retrospectively measured TMT in 99 consecutive brain MRIs from untreated patients with PCNSL. We generated a receiver operator characteristic curve and chose a single threshold defining thin TMT in all patients as <5.65 mm, at which specificity and sensitivity for 1-year progression were 98.4% and 29.7% and for 1-year mortality were 97.4% and 43.5% respectively. Those with thin TMT were both more likely to progress (P < .001) and had higher rates of mortality (P < .001). These effects were independent of the effect of age, sex, and Eastern Cooperative Oncology Group performance status in a cox regression. Memorial Sloan Kettering Cancer Center score did not predict progression-free survival or overall survival as well as TMT. Patients with thin TMT received fewer cycles of high-dose methotrexate and were less likely to receive consolidation but neither variable could be included in the Cox regression due to violation of the proportional hazards assumption. We conclude that PCNSL patients with thin TMT are at high risk for early relapse and short survival. Future trials should stratify patients by TMT to avoid confounding.

A single-arm, phase 2 study of perioperative ipilimumab, nivolumab, and cryoablation in women with hormone receptor-negative, HER2-negative, early-stage/resectable breast cancer.

TPS617 Background: Local tumor destruction with cryoablation (cryo) induces inflammation and releases antigens that can activate tumor-specific immune responses. Pre-clinically, cryo with checkpoint inhibition augmented tumor-specific immune responses and prevented recurrence. Clinically, we established that peri-operative (peri-op) cryo with ipilimumab (ipi) +/- nivolumab (nivo) was not only safe in patients (pts) with operable, early stage breast cancer (ESBC) but also generated robust intra-tumoral and systemic immune responses. In this phase 2 study, we evaluate the disease specific impact of peri-op ipi/nivo/cryo in women with residual triple negative breast cancer (TNBC) after neoadjuvant chemotherapy (NAC), a subset at high risk of early relapse. Methods: Eligible pts are ≥18y, with ER &lt; 10%, PR &lt; 10%, HER2 negative (per ASCO/CAP definition), ≥ 1.0 cm, residual operable disease after taxane-based NAC. Approximately 80 pts will be enrolled and treated with ipi/nivo/cryo followed by breast surgery and adjuvant nivo. Pts undergo percutaneous, image-guided cryo with concurrent research core biopsy 7-10 days prior to surgery and will receive ipi (1mg/kg IV) with nivo (240mg IV) 1 to 5 days prior to cryo. After surgery, pts will receive 3 additional doses of nivo at 240mg IV Q2 weeks. Adjuvant capecitabine is recommended for all patients per local standard-of-care. Patients will be stratified by NAC platinum administration, NAC anthracycline administration, and clinical nodal status (positive versus negative). The primary endpoint is 3-year Event Free Survival (EFS). Secondary endpoints include Invasive Disease-Free Survival (IDFS), Distant Disease-Free Survival (DDFS), overall survival (OS) and safety. Exploratory correlative studies will be performed on tumor and serum to characterize the immunologic impact of the intervention and to explore predictors of efficacy and toxicity. Clinical trial information: NCT03546686.

Validation of MiROvaR, a microRNA-based predictor of early relapse in early stage epithelial ovarian cancer as a new strategy to optimise patients' prognostic assessment

AimEarly-stage epithelial ovarian cancer (eEOC) patients have a generally favorable prognosis but unpredictable recurrence. Accurate prediction of risk of relapse is still a major concern, essentially to avoid overtreatment. Our robust tissue-based miRNA signature named MiROvaR, predicting early EOC recurrence in mostly advanced-stage EOC patients, is here challenged in an independent cohort to extend its classifying ability in the early-stage EOC setting. MethodsWe retrospectively selected patients who underwent comprehensive surgical staging at our institution including stages from IA to IIB. miRNA expression profile was analysed in 89 cases and MiROvaR algorithm was applied using the previously validated cut-off for patients' classification. The primary endpoint was progression-free survival (PFS) at 5 years. Complete follow-up time (median = 112 months) was also considered as secondary analysis. ResultsMiROvaR was assessable on 87 cases (19 events of disease progression) and classified 68 (78%) low-risk and 19 (22%) high-risk patients. Recurrence rate at primary end-point was 39% for high-risk patients as compared to 9.5% for low-risk ones. Accordingly, their Kaplan–Meier PFS curves were significantly different at both primary and secondary analysis (p = 0.0006 and p = 0.03, respectively). While none of the prominent clinical variables had prognostic relevance, MiROvaR significantly predicted disease recurrence at the 5-year assessment (primary endpoint analysis; HR:5.43, 95%CI:1.82–16.1, p = 0.0024; AUC = 0.78, 95%CI:0.53–0.82) and at complete follow-up time (HR:2.67, 95%CI:1.04–6.8, p = 0.041; AUC:0.68, 95%CI:0.52–0.82). ConclusionsWe validated MiROvaR performance in identifying at diagnosis eEOC patients' at higher risk of early relapse thus enabling selection of the most effective therapeutic approach.

A Novel Early Relapse Prediction Score Based on Age, ISS and Disease Status at the Time of Transplant in Patients with Newly Diagnosed Multiple Myeloma. a Study of the EBMT Chronic Malignancies Working Party

A Novel Early Relapse Prediction Score Based on Age, ISS and Disease Status at the Time of Transplant in Patients with Newly Diagnosed Multiple Myeloma. a Study of the EBMT Chronic Malignancies Working Party

A tumor microenvironment-related mRNA-ncRNA signature for prediction early relapse and chemotherapeutic sensitivity in early-stage lung adenocarcinoma.

Postoperative early relapse of early-stage lung adenocarcinoma is implicated in poor prognosis. The purpose of our study was to develop an integrated mRNA and non-coding RNA (ncRNA) signature to identify patients at high risk of early relapse in stage I-II lung adenocarcinoma who underwent complete resection. Early-stage lung adenocarcinoma data from Gene Expression Omnibus database were divided into training set and testing set. Propensity score matching analysis was performed between patients in early relapse group and long-term nonrelapse group from training set. Transcriptome analysis, random survival forest and LASSO Cox regression model were used to build an early relapse-related multigene signature. The robustness of the signature was evaluated in testing set and RNA-Seq dataset from The Cancer Genome Atlas (TCGA). The chemotherapy sensitivity, tumor microenvironment and mutation landscape related to the signature were explored using bioinformatics analysis. Twelve mRNAs and one ncRNA were selected. The multigene signature achieved a strong power for early relapse prediction in training set (HR 3.19, 95% CI 2.16-4.72, P < 0.001) and testing set (HR 2.91, 95% CI 1.63-5.20, P = 0.002). Decision curve analyses revealed that the signature had a good clinical usefulness. Groups divided by the signature exhibited different chemotherapy sensitivity, tumor microenvironment characteristics and mutation landscapes. Our results indicated that the integrated mRNA-ncRNA signature may be an innovative biomarker to predict early relapse of early-stage lung adenocarcinoma, and may provide more effective treatment strategies.