Disease-free Survival In Patients Research Articles

The association between referral by specialists in oral diagnosis on survival rates of patients with oral cancer: A retrospective cohort study.

To assess the influence of diagnosis and referral provided by specialists in oral diagnosis on disease-free survival and overall survival of patients with oral cancer. A cohort of 282 patients with oral cancer treated at a regional cancer hospital from 1998 to 2016 was analyzed retrospectively. The referral register of the patients was analyzed and assigned to two groups: (1) those referred by oral diagnosis specialists (n = 129), or (2) those referred by nonspecialized professionals (n = 153). The cancer treatment evolution was assessed from the patients' records, and the outcome was registered concerning cancer recurrence and death. Sociodemographic and clinicopathological variables were explored as predictors of disease-free survival and overall survival. Group 1 exhibited lower T stages and a reduced incidence of regional and distant metastases. Surgery was performed in 75.2% of cases in Group 1, while in Group 2, the rate was 60.8%. Advanced T stages and regional metastases reduced the feasibility of surgery. Higher TNM stages and tumor recurrence were associated with decreased disease-free survival, while surgical intervention was a protective factor. Higher TNM stage had a negative impact on the overall survival. Specialized oral diagnosis did not directly impact disease-free survival and overall survival and did not influence the indication of surgery in oral cancer; however, it was associated with the diagnosis of early tumors and better prognosis.

ALKBH5-mediated m6A modification of circFOXP1 promotes gastric cancer progression by regulating SOX4 expression and sponging miR-338-3p

Circular RNAs (circRNAs) have recently been suggested as potential functional modulators of cellular physiology processes in gastric cancer (GC). In this study, we demonstrated that circFOXP1 was more highly expressed in GC tissues. High circFOXP1 expression was positively associated with tumor size, lymph node metastasis, TNM stage, and poor prognosis in patients with GC. Cox multivariate analysis revealed that higher circFOXP1 expression was an independent risk factor for disease-free survival (DFS) and overall survival (OS) in GC patients. Functional studies showed that increased circFOXP1 expression promoted cell proliferation, cell invasion, and cell cycle progression in GC in vitro. In vivo, the knockdown of circFOXP1 inhibited tumor growth. Mechanistically, we observed ALKBH5-mediated m6A modification of circFOXP1 and circFOXP1 promoted GC progression by regulating SOX4 expression and sponging miR-338-3p in GC cells. Thus, our findings highlight that circFOXP1 could serve as a novel diagnostic and prognostic biomarker and potential therapeutic target for GC.

Preferences of physicians for treatment-related toxicity vs. recurrence in melanoma (GERMELATOX-A): the doctors’ perspective

IntroductionAdjuvant treatment with immune checkpoint inhibitors, such as PD1-antibodies (ICI) ± CTLA4-antibodies (cICI) or targeted therapy with BRAF/MEK inhibitors (TT), has shown a significant improvement in disease-free survival (DFS) for high-risk melanoma patients. However, due to specific side effects, the choice of treatment is often influenced by the risk of toxicity. Therefore, the role of physicians in treatment decisions of patients is crucial. This study investigated for the first time in a multicenter setting the attitudes and preferences of dermatooncologists in Germany and Switzerland regarding adjuvant treatment with (c)ICI and TT.MethodsIn the GERMELATOX-A study, 108 physicians (median age: 32 yrs, 67.6% female) from 11 skin cancer centers were surveyed to rate typical side effect scenarios of (c)ICI and TT treatments and then compared to patients’ ratings evaluated in a previous analysis from the same centers. The scenarios described mild-to-moderate or severe toxicity and included melanoma relapse leading to death. The physicians were asked about the level of side effects they would tolerate in exchange for a reduction in melanoma relapse and an increase in survival at 5 years.ResultsThe preferences of physicians and patients revealed significant differences regarding adjuvant melanoma treatment with (c)ICI and TT (p < 0.05). Compared to patients, physicians tend to value a melanoma relapse less severe, according to a visual analog scale. They were also less threatened by all scenarios of side effects during adjuvant treatment with (c)ICI or TT, compared to patients. Physicians required lower risk reductions for disease-free survival (DFS) and overall survival (OS) for both ICI and TT and their drug-related side effects to accept these treatments. In case of severe side effects, physicians required similar 5-year DFS rates for ICI and TT (60–65%), while patients needed a 15% improvement of 5-year DFS for ICI compared to TT (80%/65%). For survival, physicians expected an OS improvement of + 10% for all three treatment modalities, whereas patients required a higher increase: + 18–22% for ICI and + 15% for TT.ConclusionOur study highlights the importance of understanding the patient’s perspective and a potential difference to the doctor’s view when making decisions about adjuvant melanoma treatment with (c)ICI and TT, especially as these treatments are increasingly being implemented in earlier stages.

Neoadjuvant chemotherapy is associated with improved disease-free survival in pancreatic cancer patients undergoing pancreaticoduodenectomy with vascular resection.

Neoadjuvant chemotherapy (NAC) is becoming favored for all pancreatic adenocarcinoma (PDAC). Patients with seemingly resectable disease infrequently still display vascular involvement intraoperatively. Outcomes following NAC versus upfront surgery in patients undergoing pancreaticoduodenectomy (PD) with vascular resection are unknown. We performed a retrospective cohort study of PDAC patients who underwent PD with vascular resection between January 1, 2013, to December 31, 2020, within a single academic center. Clinicopathologic characteristics and disease-free survival (DFS) were compared between NAC versus upfront surgery cohorts using the Kaplan-Meier estimate and Cox proportional-hazards regression model. Eighty-one patients who underwent PD with vascular resection for PDAC were included. Forty-six patients (56%) received NAC. The NAC cohort more often had pathologic N0 status (47.8% vs. 8.6%, p < 0.001), had decreased vascular invasion (11% vs. 40%, p = 0.002), and completed chemotherapy (80% vs. 40%, p < 0.01). The NAC cohort demonstrated improved DFS (40.5 vs. 14.3 months, p = 0.007). In multivariable analysis, NAC remained independently associated with increased DFS (HR = 0.48, p = 0.02). NAC was associated with improved clinicopathologic outcomes and DFS in PD with vascular resection. These findings demonstrate the advantage of NAC in PDAC patients undergoing PD with vascular resection.

Abstract PO1-02-04: The efficacy of endocrine therapy during the waiting period for surgery for hormone receptor-positive breast cancer

Abstract Background: Although neoadjuvant endocrine therapy has been used to improve breast conservation rate, its prognostic relevance is unknown. The search for a valid prognostic factor equivalent to pCR in neoadjuvant chemotherapy is a current challenge in neoadjuvant endocrine therapy. In this study, we investigated the efficacy of short term neoadjuvant endocrine therapy utilizing the waiting period for surgery and the prognostic factor including Preoperative Endocrine Prognostic Index (PEPI) score. Methods: A total of 480 patients with StageⅠ-Ⅲ hormone receptor-positive, HER2-negative breast cancer was treated with endocrine therapy during the waiting period for surgery between October 2012 and December 2021. Premenopausal and postmenopausal patients received tamoxifen (TAM) and non-steroidal aromatase inhibitor (AI), respectively. The primary endpoint was change in tumor size by ultrasound and Ki67 expression before and after short term endocrine therapy. The secondary endpoint was prognosis of patients divided by PEPI score which was calculated using tumor size, lymph node metastasis, Ki67 expression, and ER Allred score. This study was approved by the institutional review board of Teikyo University. Results: Median age and tumor size of the entire 480 patients was 55 years (range, 31 - 89), 1.65 cm (range, 0.4 – 7.5), respectively. The median duration of endocrine therapy was 39 days (range, 1-90). 19 (0.3 %) pts were clinically node-positive. Of the entire 480 patients, 211 and 269 patients had TAM and AI, respectively. After short term endocrine therapy, the tumor size was significantly reduced from 1.83cm to 1.62cm in AI group (p=0.02), although TAM did not decrease the tumor size (p=0.89). The Ki67 expression was significantly decreased from 16.4% to 11.3% in TAM group (p=0.002), and from 15.9% to 6.98% in AI group (p &amp;lt; 0.001). There were significant differences in the distribution of PEPI scores between TAM and AI group (p &amp;lt; 0.05) (Table). At the median follow-up of 1012 days, patients with PEPI score ≥ 4 showed worse disease-free survival compared with patients with PEPI score &amp;lt; 4 in TAM group (Figure1). Overall survival is not available because there were no deaths in TAM group. At the median observation period of 833 days, patients with PEPI score ≥ 4 showed worse disease-free survival compared with patients with PEPI score &amp;lt; 4 in AI group (Figure2). In terms of mortality, patients with PEPI score ≥ 4 had worse overall survival than patients with PEPI score 0 and 1-3 (p=0.07). Conclusions: These results suggested that neoadjuvant endocrine therapy during the waiting period for surgery might be effective in reducing Ki67 expression level and PEPI score might be useful in predicting the prognosis of hormone receptor positive breast cancer patients. Table. Distribution of PEPI score Figure 1. Disease-free survival in patients treated with tamoxifen Figure 2. Disease-free survival in patients treated with non-steroidal aromatase inhibitor Citation Format: Yuka Maeda, Saki Naruse, Yuka Isono, Ayana Sato, Akiko Matsumoto, Tatsuhiko Ikeda, Hiromitsu Jinno. The efficacy of endocrine therapy during the waiting period for surgery for hormone receptor-positive 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 PO1-02-04.

Abstract PO5-25-03: Immune cell infiltrate profiles in primary Triple Negative Breast Cancer and co-relation with treatment response and survival outcomes

Abstract Introduction Tumor microenvironment (TME) in breast cancer is a heterogeneous landscape with multiple cell types, each modulating the tumor progression and the disease prognosis. These cell types include lymphocytes, RBCs, stromal cells, macrophages, cancer-associated fibroblasts (CAFs), and cancer stem cells. Each cell type in the TME influences tumor progression and clinical outcomes for patients in a good or bad way, depending on the interaction with tumor cells. Tumor-infiltrating lymphocytes (TILs) are shown to be prognostic for therapy response in many cancers in the western cohorts. Our recent study showed that a higher proportion of Indian TNBC patients had intra-tumoral TILs compared to Western cohorts, and these are predictive of better response to NACT and longer disease-free survival in patients, making it a distinct finding from Western reports. In the follow-up study, we are characterizing infiltrating immune cell subtypes and their comparative association with treatment response in TNBC patients. Results from preliminary analysis and comparative analysis between responders and non-responders will be presented here. We speculate that the pro- and anti-tumorigenic immune cell population and its spatial information would help us understand TME and its precise role in response to therapy. Methods A retrospective cohort of breast cancer patients from a single one-surgeon breast cancer clinic with a uniform treatment strategy was evaluated for this study. FFPE primary tissue samples with variable TILs scores (moderate to high), taken from patients who showed complete response to the NACT treatment (n=6) and non-responding group (n=8) determined by H&amp;E stained slides from our cohort, were further stained for immune cells (Pan-B cell, Pan-T cells, Pan-macrophages) and T cells (CD4; Helper T cell marker, CD8; Cytotoxic T cell marker), FOXP; Regularly CD4+ cell marker) and PanCK (Pan-tumor marker) and counterstained with DAPI for multiplex imaging. Multispectral images for these slides were obtained using the Leica Aperio Versa system. Parameters such as individual cell types of identification and scoring, spatial proximity to tumor cells, and individual cell types will be determined by HALO software using the High plex module. Results A total of 14 TNBC samples were stained for the T-cell subtypes panel and Immune cell subtype s panel to determine the TIME. DAPI stain was used for nuclear counting based the parameters such as threshold intensity, nuclear size, roundness, and aggressiveness. The cytoplasmic size was selected as 2um beyond the outside nuclear boundary. Using Halo-Indica software, around 50000-300000 cells/tissue were evaluated across all samples from mIF whole slide scans of biopsy samples. Cell count was validated by cross-checking individual ROIs and manual cell count using Fiji. A Highplex module was used to identify individual signal positivity for each marker based on threshold intensity and cell completeness percent. Preliminary data showed a higher proportion of CD8+ cells and macrophages population are spatially closer to the tumor cells in Responders compared to non-responders. Conclusion Immune profiles are distinct among responding and non-responding patients in the Indian TNBC cohort. The association of these profiles with long-term survival in patients and various clinical and pathological parameters will help us determine the clinical relevance of these profiles and identify distinct immune subgroups as prognostic in Indian TNBCs. Citation Format: Pooja Vaid, Devaki Kelkar, LS Shashidhara, C B Koppiker, Madhura Kulkarni. Immune cell infiltrate profiles in primary Triple Negative Breast Cancer and co-relation with treatment response and survival outcomes [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 PO5-25-03.

Abstract PO4-01-01: Prognostic Impact of Adjuvant Trastuzumab for the Treatment of Localized Stage I Breast Cancer - Single Tertiary Center Experience

Abstract Prognostic Impact of Adjuvant Trastuzumab for the Treatment of Localized Stage I Breast Cancer – Single Tertiary Center Experience Sasha Sapon-Cousineau, Marie Florescu, Danielle Charpentier, Rami Younan, Erica Patocskai, Saima Hassan, Kerianne Boulva, Jean-Pierre Ayoub Centre hospitalier de l’Université de Montréal, Montréal, Québec, Canada The HER2 oncoprotein is an established therapeutic target, and the combination of adjuvant chemotherapy and targeted anti-HER2 therapy substantially reduces the risk of recurrence and death over chemotherapy alone in high-risk operable breast cancers that overexpress HER2. However, most studies demonstrating the benefits of anti-HER2 treatments have focused on cohorts at high risk of recurrence. Limited data exists for low-risk cancers to justify this treatment. We performed a retrospective study from 263 patients treated at our oncology center at the Centre hospitalier de l’Université de Montréal between 2006 and 2019 for HER2-positive, N0 or N0(i+) and T1mic to T1c breast cancers. A total of 227 patients were included, 149 (57%) with anti-HER2 treatment and 78 (30%) without. Patients had a single site of HER2-overexpressing invasive breast neoplasia with a follow-up of at least 6 months. Primary outcome was overall survival. Secondary outcomes were disease-free survival and the impact of tumoral and demographic factors. Median follow-up period was 6.7 years. Overall survival at 5 years was 97% (CI 94, 100) for the group with anti-HER2 treatment versus 92% (CI 85, 98) for the group without anti-HER2 treatment. The difference in overall survival between the two treatment groups increased with tumor size. Disease-free survival at 5 years was 93% (CI 88, 87) for the group with anti-HER2 treatment versus 82% (CI 74, 92) for the group without anti-HER2 treatment. In subgroup analysis, age and tumor size had a significant impact on the difference in disease-free survival between groups. Our study demonstrates the significant impact of anti-HER2 targeted therapies on overall survival and disease-free survival for patients with small, HER2 positive localized breast cancers. Further benefit is seen in certain subgroups, such as older patients and those with tumors larger than 1.0 cm, and this should be considered when determining appropriate treatment. Citation Format: Sasha Sapon-Cousineau, Marie Florescu, Danielle Charpentier, Rami Younan, Erica Patocskai, Saima Hassan, Kerianne Boulva, Jean-Pierre Ayoub. Prognostic Impact of Adjuvant Trastuzumab for the Treatment of Localized Stage I Breast Cancer - Single Tertiary Center Experience [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 PO4-01-01.

Abstract GS03-06: Genomic and transcriptomic profiling of primary tumors from patients with HR+, HER2-, node-positive, high-risk early breast cancer in the monarchE trial

Abstract Background Two years of adjuvant abemaciclib combined with endocrine therapy (ET) resulted in significant and clinically meaningful improvement in invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) in patients (pts) with HR+, HER2-, node-positive, high-risk early breast cancer in the monarchE trial (NCT03155997). Abemaciclib benefit was sustained beyond the completion of treatment (tx) with deepening magnitude of absolute benefit in IDFS and DRFS at 5 years. Here, we evaluate comprehensive molecular profiling of archived primary tumor tissue and association with clinical outcomes. Methods For biomarker analysis, a proportionally stratified random sampling case-cohort design was utilized to include all patients who experienced an IDFS event at a pre-specified interim analysis with a median follow up of 54 months. A cohort of 895 pts (189 with IDFS event) in the abemaciclib + ET arm was matched 1:1 with 903 pts (270 with IDFS event) in the ET arm. Baseline primary tumor samples underwent exome-capture RNA sequencing (RNAseq; n=1324, 23% intent-to-treat (ITT) population) and paired tumor-normal (germline blood samples) whole-exome sequencing (WES; n=1234, 22% ITT population). Expression-based intrinsic subtypes (i.e., luminal A (LumA), luminal B (LumB), HER2-enriched (HER2E), basal- and normal-like) were characterized using the Absolute Intrinsic Molecular Subtyping model. The 21-gene expression signature score (Oncotype DX test) was inferred from RNAseq; samples were categorized into lower (0-25) and high (26-100) risk groups. To investigate associations of biomarkers with abemaciclib benefit, WES genomic events including oncogenic and hotspot mutations by OncoKB, and copy number events, of incidence &amp;gt;9% were pre-selected. Results The biomarker subset of monarchE was reflective of the ITT population. A total of 1190 tumors (abemaciclib+ET n= 605; ET alone n=585) yielded adequate RNAseq results. Intrinsic subtype distribution was consistent across tx arms (Table A). Low tumor purity limited assessment of the normal-like subtype. The 4-year IDFS benefit of abemaciclib was consistent across all subtypes. LumA cancers had the lowest risk of recurrence while HER2E and basal-like subtypes had the highest. Inferred 21-gene expression signature score showed similar benefits from abemaciclib in both lower and high-risk groups (Table B). A total of 1173 tumors yielded adequate WES results (abemaciclib+ET n=580; ET alone n=593). Consistent abemaciclib benefit was observed across the most frequently altered genes (Table C). In exploratory analysis, lower benefit from abemaciclib was seen in the subset of focal-high level MYC amplified tumors (n=176, HR 1.30, 95% CI, 0.77, 2.20) compared to MYC non-amplified tumors (n=997, HR 0.62, 95% CI, 0.47, 0.80, nominal interaction p=0.014). The treatment benefit of abemaciclib was observed across all subpopulations of altered genes based on gene expression data. Conclusions Adjuvant abemaciclib+ET maintained IDFS benefit compared to ET alone across all molecular subtypes as measured by RNAseq. Benefit was consistent across most altered genes assessed by WES, except for the subset of tumors with MYC amplification. Additional research is necessary to confirm these findings. Table. Citation Format: Nicholas Turner, Jorge Reis-Filho, Matthew Goetz, Christine Desmedt, Sarat Chandarlapaty, Hironobu Sasano, Carlos Arteaga, Sherene Loi, Stephanie Graff, Deli Liu, Vanessa Rodrik-Outmezguine, Anthony Sireci, Cynthia Sandoval Rubenstein, Helen Won, Lacey M. Litchfield, Maria Munoz, Stephen Johnston. Genomic and transcriptomic profiling of primary tumors from patients with HR+, HER2-, node-positive, high-risk early breast cancer in the monarchE 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 GS03-06.

Abstract PS06-01: Results from a pilot study exploring ctDNA detection using a tumor-informed assay in the monarchE trial of adjuvant abemaciclib with endocrine therapy in HR+, HER2-, node-positive, high-risk early breast cancer

Abstract Background Two years of adjuvant abemaciclib + endocrine therapy (ET) resulted in significant and clinically meaningful improvement in invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) in patients (pts) with HR+, HER2-, node-positive, high-risk early breast cancer (EBC) in the monarchE trial (NCT03155997). The benefit of abemaciclib was sustained beyond completion of treatment and deepened in magnitude at 4 years for IDFS and DRFS. This pilot study investigated the technical feasibility of ctDNA detection beginning prior to study treatment, as well as rates of persistence and clearance in a subset of EBC pts from monarchE using the clinically validated SignateraTM ctDNA assay. Methods Samples were analyzed from a selected subset of pts (n=178; 84 from abemaciclib+ET arm; 94 ET alone) who had blood collected both before initiating protocol directed therapy, Visit 1 (V1; randomization + ≤ 3 days) and near completion of the 2-year treatment period, Visit 27 (V27; 24 months +/- 5 days from V1). This cohort of pts was enriched for overall IDFS events compared to the total monarchE study population, however pts with relapses occurring prior to V27 were excluded. Primary tumors from selected pts were subjected to whole exome sequencing (WES). Selected samples included those from pts with a range of tumor mutation burden. Cell-free DNA was extracted from 356 plasma samples. A Signatera ctDNA assay was developed for each pt based on up to 16 variants detected by WES from each baseline tumor sample. Results The IDFS event rate for the selected subset (n=178) was 39.3% (abemaciclib+ET 34.5% [29/84] and ET alone 43.6% [41/94]). Ten pts (5.6%) were initially ctDNA+ and 42 pts (23.6%) were persistently (7 pts, 3.9%) or became (35 pts, 19.7%) ctDNA+ at V27. Notably, 70% of pts who were initially ctDNA+ and 100% of pts who were either persistently ctDNA+ or became ctDNA+ experienced recurrence (see Table 1). In contrast, none of the 3 pts that cleared ctDNA+ developed recurrence. In pts persistently ctDNA negative (neg), 28 (21.1%) experienced recurrence. Overall, 10% (7/70) of pts with IDFS events were initially ctDNA+ and 50% (35/70) had detectable ctDNA at V27. Conclusions Detection of ctDNA soon after completing neoadjuvant chemotherapy was infrequent, but also associated with a high-risk of recurrence. ctDNA positivity was common at the end of the 2-year treatment period and was highly prognostic with all pts subsequently developing disease recurrence. Importantly, ~30% of pts with early ctDNA detection ultimately dropped below detection limits during the 2-year treatment period and none developed recurrence. Although some pts remained persistently ctDNA neg during this study and experienced recurrence, the delay in recurrence may indicate longitudinal benefit from remaining ctDNA neg. Future planned analysis of an expanded cohort reflective of the intent to treat population including additional timepoints within the 2-year treatment period will further define how ctDNA dynamics may identify pts at high-risk of recurrence. Table 1. Summary of Subset Positivity Rates. + positive; - negative; NA, not applicable. Citation Format: Sherene Loi, Stephen Johnston, Carlos Arteaga, Stephanie Graff, Sarat Chandarlapaty, Matthew Goetz, Christine Desmedt, Jorge Reis-Filho, Hironobu Sasano, Vanessa Rodrik-Outmezguine, Anthony Sireci, Cynthia Sandoval Rubenstein, Helen Won, Deli Liu, Lacey M. Litchfield, Nicholas Turner. Results from a pilot study exploring ctDNA detection using a tumor-informed assay in the monarchE trial of adjuvant abemaciclib with endocrine therapy in HR+, HER2-, node-positive, high-risk early 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 PS06-01.

Abstract PO4-16-08: Prognostic factors for tumor recurrence after breast-conserving and radiotherapy treatment for early invasive breast cancer: ten years of results in a referral center in Mexico City

Abstract Background: Breast cancer is the most common malignancy in the world, reporting more than 2 million new cases in 2020. In early stages, patients undergo primary surgery. Breast-conserving surgery (BCS) has generally been accepted as a treatment for invasive breast cancer, findings at 20 years still show that lumpectomy and breast irradiation, as compared with mastectomy, have no significant difference in overall survival among the treatment groups. Approximately 10-15% of patients will develop local or systemic recurrence in 5 to 10 years. Factors such as young age (&amp;lt; 45 years), close/positive margins, no breast radiation, are associated with ipsilateral breast tumor recurrence. High grade has been related to distant metastasis. The mortality trend is upward due to a higher incidence of the disease and earlier detection. Methods: This is an observational and retrospective cohort study, which included patients with early breast cancer, who were treated with conserving surgery and received radiotherapy, at the Breast Oncology Service at the UMAE Gineco 4 "Luis Castelazo Ayala" during the period from January 2012 to December 2022. The aim of our study was to describe the prognostic factors associated with disease-free survival (DFS) and overall survival (OS) in patients with localized breast cancer treated with BCS. DFS was defined as time from surgery to recurrence event (local recurrence, distant recurrence, contralateral breast cancer, second primary cancer, or death from any cause) whichever occurred first. For statistical analysis, Kaplan Meier and Log-rank methods were used for survival analysis. Cox proportional hazard model was used for multivariate analysis. Results: We included 399 patients, the median follow-up was 88 months (95%CI 86-91). Median age was 59 years. The most common pathological stage was IA in 44.9%, the predominant immunophenotype was luminal A in 56.1% of patients, follow by luminal B in 19.3% and 13% were triple negative. Management of axilla with sentinel node biopsy occurred in 50.1% and 49.9% underwent to lymph node dissection. Regarding surgery outcomes 40.4% of the patients required widening of the margins, 5% of the patients remained with close surgical margins ≤2 mm, 7.5% had complications associated with the surgery, and none related death ocurred. All patients received adjuvant radiotherapy, the median time to initiation was 32 weeks (range 3-70) and 65.4% received adjuvant chemotherapy. Recurrence events occurred in 15.5% of patients, local 2.8%, systemic 8.8%, contralateral breast cancer 1.7%, and second primary 2.2%. Estimated disease-free survival at 5 and 10 years were 86.6% and 74.2%, respectively. In the multivariate analysis independent prognostic factors for DFS were: lobular histology HR 2.95 (95%IC 1.5-5.7), tumor size ≥ 2cm HR 1.95 (95%IC 1.1-3.6), close surgical margins HR 2.62 (95%IC 1-6.6), and ER low expression (1-10%) HR 4.39 (95%CI: 1.6-12.4). Estimated OS at 5 and 10 years for patients who experienced recurrence were 78.4% and 47.4% and for patients without recurrence were 96.8% and 93.5%, respectively (adjusted HR: 10.4, 95%CI: 5.2-20.6). Conclusion: These results suggest that patients with early breast cancer treated with conserving surgery and radiotherapy with risk factors such as lobular carcinoma, tumor size ≥2cm, close margins, and low expression of estrogen receptors have a high risk of recurrence and significantly decreased overall survival at 5 and 10 years. Citation Format: Nayeli Ortega-Avila, Yuly A. Remolina-Bonilla, Janett Caballero-Jasso. Prognostic factors for tumor recurrence after breast-conserving and radiotherapy treatment for early invasive breast cancer: ten years of results in a referral center in Mexico City [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 PO4-16-08.

Abstract PO4-22-04: Evaluation of acute toxicity in breast cancer patients receiving concurrent capecitabine and radiation

Abstract Purpose: Adjuvant capecitabine has been shown to improve disease-free survival and overall survival in breast cancer patients who have residual disease after neoadjuvant chemotherapy, particularly in those with triple negative breast cancer (TNBC). While adjuvant chemotherapy is often completed prior to adjuvant radiotherapy (RT), capecitabine may be administered concurrent with RT to reduce the time from surgery to RT. The purpose of this study was to evaluate the feasibility of concurrent therapy and the associated rates of acute loco-regional toxicity. Materials and Methods: A retrospective chart review was performed to identify all breast cancer patients who received adjuvant capecitabine and RT. Patients with a history of prior RT, patients who were treated with capecitabine and RT sequentially, and patients who were treated with palliative intent were excluded. Capecitabine was given Monday-Friday during RT. Patient and disease characteristics, capecitabine and RT treatment details, acute toxicity, and treatment breaks were recorded. Toxicity was scored by the Common Terminology Criteria for Adverse Events (CTCAE) version 5. Results: A total of 27 patients with non-metastatic breast cancer who received concurrent capecitabine and RT with definitive intent treated from 2013 to 2023 were identified. Median age at diagnosis was 52 years [Interquartile Range (IQR) 40-60]. Adjuvant capecitabine dose ranged from 500-1500 mg twice daily. Adjuvant RT dose ranged from 42.56 Gray (Gy) to 50.4Gy. The majority of patients (92.6%) received a sequential 10-14 Gy boost to the lumpectomy site or mastectomy scar, and 70.3% of patients received elective regional nodal RT. During treatment, all patients developed Grade 1 or 2 radiation dermatitis, while Grade 3 radiation dermatitis was noted in 4 (14.8%) patients. Two patients required a treatment break from RT, and both patients were able to subsequently complete their planned RT course. Seven patients (25.9%) required a capecitabine dose reduction or capecitabine treatment break during RT. No Grade 4 or 5 toxicities were reported. Median follow-up from RT completion was 7 months [IQR 0.98-12.2]. At last follow-up, radiation dermatitis had improved to Grade 0-1 for all patients. Conclusion: Concurrent adjuvant capecitabine and RT is a feasible treatment approach that is well tolerated with acceptable acute toxicities. Citation Format: Ahmed Shalaby, Zohaib Sherwani, Lara Hathout, Imraan Jan, Bruce Haffty, Mridula George, Shicha Kumar, Coral Omene, Deborah Toppmeyer, Nisha Ohri. Evaluation of acute toxicity in breast cancer patients receiving concurrent capecitabine and radiation [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 PO4-22-04.

Transcriptome analysis reveals PRKCA as a potential therapeutic target for overcoming cisplatin resistance in lung cancer through ferroptosis

Cisplatin-based chemotherapy is the current standard care for lung cancer patients; however, drug resistance frequently develops during treatment, thereby limiting therapeutic efficacy.The molecular mechanisms underlying cisplatin resistance remain elusive. In this study, we conducted an analysis of microarray data from the Gene Expression Omnibus (GEO) database under the accession numbers GSE21656, which encompassed expression profiling of cisplatin-resistant H460 (DDP-H460)and the parental cells (H460). Subsequently, we calculated the differentially expressed genes (DEGs) between DDP-H460 and H460. Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of DEGs demonstrated significant impact on the Rap1, PI3K/AKT and MAPK signaling pathways. Moreover, protein and protein interaction (PPI) network analysis identified PRKCA, DET1, and UBE2N as hub genes that potentially contribute predominantly to cisplatin resistance. Ultimately, PRKCA was selected for validation due to its significant prognostic effect, which predicts unfavorable overall survival and disease-free survival in patients with lung cancer. Network analysis conducted on The Cancer Genome Atlas (TCGA) database revealed a strong gene-level correlation between PRKCA and TP53, CDKN2A, BYR2, TTN, KRAS, and PIK3CA; whereas at the protein level, it exhibited a high correlation with EGFR, Lck, Bcl2, and Syk. The in vitro experiments revealed that PRKCA was upregulated in the cisplatin-resistant A549 cells (DDP-A549), while knockdown of PRKCA increased DDP-A549 apoptosis upon cisplatin treatment. Moreover, we observed that PRKCA knockdown attenuated DDP-A549 proliferation, migration and invasion ability. Western blot analysis demonstrated that PRKCA knockdown downregulated phosphorylation of PI3K expression while upregulated the genes involved in ferroptosis signaling. In summary, our results elucidate the role of PRKCA in acquiring resistance to cisplatin and underscore its potential as a therapeutic target for cisplatin-resistant lung cancer.

Size of extranodal extension in the sentinel lymph node as a predictor of prognosis in early-stage breast cancer

IntroductionThe presence of extranodal extension (ENE) in sentinel lymph nodes (SLNs) can predict non-SLN metastases in breast cancer (BC) patients; however, the prognostic relevance of its extent remains controversial. The purpose of this study was to examine the predictive role of ENE in SLNs measured by its widest dimension (WD), highest dimension (HD), and the WD/HD ratio for non-SLN involvement, overall, and disease-free survival (OS, DFS) in cT1-2N0 BC patients with positive SLNs. Materials and MethodsA total of 511 women with cT1-2N0 BC and positive SLNs undergoing axillary lymph node dissection were retrospectively enrolled. The associations of ENE's WD, HD, and WD/HD ratio with non-SLN metastases, five-year OS, and DFS were established through a multivariable modeling approach. ResultsSLNs were ENE-positive in 149 (29.16%) participants, and 133 (26.03%) had non-SLN metastases. During the median 60 (16-60)-month follow-up, 69 (13.50%) patients experienced recurrences, and 62 (12.13%) died. The numbers of SLNs, non-SLNs, and total axillary LNs involved differed between the ENE-negative and ENE-positive groups, as well as between the WD/HD ≤1.2 and WD/HD >1.2 subgroups (all p-values were <0.001). Multivariable analyses showed significant associations of the WD/HD ratio >1.2 with non-SLN involvement, OS, and DFS (p-values were 0.003, <0.001, and 0.005, respectively). DiscussionDespite no predictive value of ENE's WD and HD, the WD/HD ratio >1.2 was an independent predictor of non-SLN involvement, mortality, and recurrence.ENE's WD/HD ratio could be a valuable indicator for cT1-2N0 BC individuals with positive SLNs for whom further axillary treatment may be beneficial. Micro abstractIn breast cancer (BC), the prognostic relevance of extranodal extension (ENE) size in sentinel nodes (SLNs) is controversial. All cT1-2N0 BC participants had SLN macrometastases; 29.16% had ENE-positive SLNs. As an independent predictor of non-SLN metastases and survival, ENE's widest dimension (WD) to highest dimension (HD) ratio >1.2 could indicate Z011-eligible BC patients who may benefit from further axillary treatment.

Identification of Hub Genes in Liver Hepatocellular Carcinoma Based on Weighted Gene Co-expression Network Analysis.

Liver hepatocellular carcinoma (LIHC) is a malignant cancer with high incidence and poor prognosis. To investigate the correlation between hub genes and progression of LIHC and to provided potential prognostic markers and therapy targets for LIHC. Our study mainly used The Cancer Genome Atlas (TCGA) LIHC database and the gene expression profiles of GSE54236 from the Gene Expression Omnibus (GEO) to explore the differential co-expression genes between LIHC and normal tissues. The differential co-expression genes were extracted by Weighted Gene Co-expression Network Analysis (WGCNA) and differential gene expression analysis methods. The Genetic Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were carried out to annotate the function of differential genes. Then the hub genes were validated using protein-protein interaction (PPI) network. And the expression level and prognostic analysis were performed. The probable associations between the expression of hub genes and both tumor purity and infiltration of immune cells were explored by TIMER. A total of 68 differential co-expression genes were extracted. These genes were mainly enriched in complement activation (biological process), collagen trimer (cellular component), carbohydrate binding and receptor ligand activity (molecular function) and cytokine - cytokine receptor interaction. Then we demonstrated that the 10 hub genes (CFP, CLEC1B, CLEC4G, CLEC4M, FCN2, FCN3, PAMR1 and TIMD4) were weakly expressed in LIHC tissues, the qRT-PCR results of clinical samples showed that six genes were significantly downregulated in LIHC patients compared with adjacent tissues. Worse overall survival (OS) and disease-free survival (DFS) in LIHC patients were associated with the lower expression of CFP, CLEC1B, FCN3 and TIMD4. Ten hub genes had positive association with tumor purity. CFP, CLEC1B, FCN3 and TIMD4 could serve as novel potential molecular targets for prognosis prediction in LIHC.

Prognostic value of postoperative anti-thyroglobulin antibody in patients with differentiated thyroid cancer.

Postoperative thyroglobulin (Tg) generally serves as a biomarker to monitor the recurrence or persistence of differentiated thyroid cancer (DTC), whereas it constrains to interference from anti-thyroglobulin antibody (TgAb). This study aimed to determine the value of postoperative TgAb as a surrogate for monitoring tumor status in DTCs with positive TgAb after successful radioactive iodine (RAI) remnant ablation. We retrospectively enrolled DTC patients with positive (≥40 IU/mL, Roche) postoperative TgAb measurements. An index of TgAb change (ΔTgAb) was defined to describe the TgAb decrease rate. DTC status was defined as either no evidence of disease (NED) or persistent/recurrent disease (PRD). Univariate and multivariate binary logistic analyses were used to identify the independent risk factors of PRD. Receiver operating characteristic (ROC) curves were performed to determine the optimal cutoff values of each risk factor, and DeLong's test was conducted to compare their predictive powers. Kaplan-Meier curves were used to assess the impact of different TgAb trends in the first year on progression-free survival. Of the 232 patients enrolled, the median diagnosis age was 34 years (range, 18-62 years), with a male-to-female ratio of 1:4.66 (41/191). Among them, after a median follow-up of 44 months (range, 4-128 months),183 (78.87%) patients were evaluated as NED, while the other 49 (21.12%) had either persistent (n = 25) or recurrent disease (n = 24). Multivariate regression showed that ΔTgAb (P < 0.001) and lymph node metastasis (LNM) rate (P = 0.009) were independently relevant to the presence of PRD, with optimal cutoff values of 47.0% and 35.1%, respectively. It is important to note that there is a high negative predictive value (96.93%) of ΔTgAb with the cutoff of 47.0%. DeLong's test showed that ΔTgAb alone and the combination of ΔTgAb and LNM rate were significantly greater than the isolated LNM rate (both P < 0.001) in predicting NED, while there was no statistical difference of the predictive power between ΔTgAb and the combination (P = 0.203). Additionally, patients with ΔTgAb >47.0% had longer progression-free survival than those with ΔTgAb ≤47.0% (not reached vs. 50 months, P < 0.001), and those with ΔTgAb >47.0% or negative conversion within the first year after RAI ablation had longer progression-free survival. Our study suggested that ΔTgAb could serve as a valuable indicator of disease status in DTC patients with positive TgAb. A ΔTgAb of >47.0% is conducive to identify those with NED and may help to obviate their overtreatment. The decrease rate and negative conversion of TgAb in the first year were good predictors of disease-free survival in patients.

Modulating DNA damage response in uveal melanoma through embryonic stem cell microenvironment

BackgroundUveal melanoma (UVM) is the most common primary intraocular tumor in adults, with a median survival of 4–5 months following metastasis. DNA damage response (DDR) upregulation in UVM, which could be linked to its frequent activation of the PI3K/AKT pathway, contributes to its treatment resistance. We have reported that embryonic stem cell microenvironments (ESCMe) can revert cancer cells to less aggressive states through downregulation of the PI3K signaling, showing promise in modulating the DDR of UVM.MethodsSince nonhomologous end joining (NHEJ) is the main DNA repair mechanism in UVM, this study utilized gene expression analysis and survival prognosis analysis to investigate the role of NHEJ-related genes in UVM based on public databases. Xenograft mouse models were established to assess the therapeutic potential of ESC transplantation and exposure to ESC-conditioned medium (ESC-CM) on key DNA repair pathways in UVM. Quantitative PCR and immunohistochemistry were used to analyze NHEJ pathway-related gene expression in UVM and surrounding normal tissues. Apoptosis in UVM tissues was evaluated using the TUNEL assay.ResultsPRKDC, KU70, XRCC5, LIG4 and PARP1 showed significant correlations with UM progression. High expression of PRKDC and XRCC5 predicted poorer overall survival, while low PARP1 and XRCC6 expression predicted better disease-free survival in UVM patients. ESCMe treatment significantly inhibited the NHEJ pathway transcriptionally and translationally and promoted apoptosis in tumor tissues in mice bearing UVM. Furthermore, ESC transplantation enhanced DDR activities in surrounding normal cells, potentially mitigating the side effects of cancer therapy. Notably, direct cell-to-cell contact with ESCs was more effective than their secreted factors in regulating the NHEJ pathway.ConclusionsOur results suggest that NHEJ-related genes might serve as prognostic markers and therapeutic targets in UVM. These findings support the therapeutic potential of ESC-based therapy in enhancing UVM sensitivity to radiochemotherapy and improving treatment outcomes while minimizing damage to healthy cells.

Resection of colorectal carcinoma liver metastases: A population-based study in outcomes and factors associated with recurrent disease

ObjectiveTo assess the hepatic disease-free survival (HDFS) and overall survival (OS) of patients who underwent resection of colorectal cancer liver metastases (CRCLM) in our population, and evaluate what factors are associated with these outcomes. MethodsPatients with resected non-mucinous CRCLM between January 2013-February 2020 were retrospectively identified. Dates of diagnosis, surgery, and, if applicable, death were recorded. HDFS and OS were calculated using a census date of 24 September 2022. Separate Cox multivariate regression analyses were performed to evaluate for association between HDFS and OS and the following factors: pre-operative imaging interval (<4 weeks vs. ≥4 weeks); pre-operative imaging modality (CT only vs. MRI+CT); extrahepatic disease at time of hepatectomy (yes vs. no); tumor burden score (TBS, where TBS2 = (largest axial dimension of CRCLM)2 + (number of CRCLM)2); pT and pN; and neoadjuvant chemotherapy. Results137 subjects (mean age, 61 ± 11 years, 86 males) were included. Associations with recurrent hepatic disease were found with chemotherapy (HR 2.11[95 % CI = 1.13–3.92]), TBS (HR 1.30[95 % CI = 1.17–1.45]), MRI+CT (HR 2.12[95 % CI = 1.29–3.48]), and extrahepatic disease at hepatectomy (HR 2.16[95 % CI = 1.08–4.35]). For mortality, associations were found with TBS (HR 1.22[95 % CI = 1.09–1.37]), pT (HR 1.45[95 % CI = 1.05–2.00]), and extrahepatic disease at hepatectomy (HR 2.10[95 % CI = 1.31–3.36]). ConclusionIn our population, non-imaging related factors TBS, neoadjuvant chemotherapy, pT and presence of extrahepatic disease at time of hepatectomy were associated with HDFS and/or OS. The preoperative imaging interval and use of preoperative MRI were not associated with improved patient outcomes.

Curative effect of percutaneous microwave ablation therapy on hepatocellular carcinoma survival: a 15-year real-world study

Objective: To evaluate the long-term efficacy of percutaneous microwave ablation (MWA) therapy for hepatocellular carcinoma. Methods: 2054 cases with Barcelona Clinic Liver Cancer (BCLC) stage 0~B at the Fifth Medical Center of the Chinese People's Liberation Army General Hospital from January 2006 to September 2020 were retrospectively collected. All patients were followed up for at least 2 years. The primary endpoint of overall survival and secondary endpoints (tumor-related survival, disease-free survival, and postoperative complications) of patients treated with ultrasound-guided percutaneous MWA were analyzed. Kaplan-Meier method was used for stratified survival rate analysis. Fine-and-Gray competing risk model was used to analyze overall survival. Results: A total of 5 503 HCC nodules [mean tumor diameter (2.6±1.6) cm] underwent 3 908 MWAs between January 2006 and September 2020, with a median follow-up time of 45.6 (24.0 -79.2) months.The technical effectiveness rate of 5 375 tumor nodules was 97.5%. The overall survival rates at 5, 10, and 15-years were 61.6%, 38.8%, and 27.0%, respectively. The tumor-specific survival rates were 67.1%, 47.2%, and 37.7%, respectively. The free tumor survival rates were 25.8%, 15.7%, and 9.9%, respectively. The incidence rate of severe complications was 2.8% (108/3 908). Further analysis showed that the technical effectiveness and survival rate over the passing three time periods from January 2006-2010, 2011-2015, and 2016-September 2020 were significantly increased, with P < 0.001, especially for liver cancer 3.1~5.0 cm (P < 0.001). Conclusion: Microwave ablation therapy is a safe and effective method for BCLC stage 0-B, with significantly enhanced technical efficacy and survival rate over time.

Prognostic role of C-reactive protein in patients with endometrial cancer: a meta-analysis.

Background: The present meta-analysis aimed to explore the association between C-reactive protein (CRP) levels and the prognosis of patients with endometrial cancer (EC). Methods: The effect of CRP level on predicting overall survival (OS) and disease-free survival (DFS) in patients with EC was evaluated according to pooled hazard ratios (HRs) and corresponding 95%CIs. Results: High CRP levels were not significantly correlated with OS (HR: 1.32 [95% CI: 0.99-1.77]; p=0.060) or DFS (HR: 1.05 [95% CI: 0.88-1.25]; p=0.597) in patients with EC. Conclusion: CRP levels did not significantly predict OS or DFS in patients with EC. However, according to subgroup analyses, higher CRP levels were significantly associated with poor OS in Asian patients with EC.

The role of transcription factor FOXA1/C2/M1/O3/P1/Q1 in breast cancer.

Breast cancer is a common malignancy with the highest mortality rate among women worldwide. Its incidence is on the rise year after year, accounting for more than one-tenth of new cancers worldwide. Increasing evidence suggests that forkhead box (FOX) transcription factors play an important role in the occurrence and development of breast cancer. However, little is known about the relationship between the expression, prognostic value, function, and immune infiltration of FOX transcription factors in tumor microenvironment. We used bioinformatics to investigate expression and function of FOX factor in breast cancer. Our results revealed the expression levels of FOXA1 and FOXM1 were significantly higher in breast cancer tissues than in normal tissues. The high expression of mRNA in FOXA1 (P < .05), FOXM1 (P < .01), and FOXP1 (P < .05) groups was related to tumor stage. Survival analysis results showed that increased FOXP1 mRNA levels were significantly associated with overall survival (OS), recurrence-free survival (RFS), and distant metastasis-free survival (DMFS) in all patients with breast cancer (P < .05). Patients with the FOXA1 high-expression group had better RFS and DMFS than the low-expression group (P < .05), while patients with FOXM1 high-expression group had worse RFS, OS, and DMFS than the low-expression group (P < .05). Meanwhile, mutation analysis showed that genetic alterations in FOX transcription factors were significantly associated with shorter OS and progression-free survival (P < .05), but not with disease-free survival (P = .710) in patients with breast cancer. FOXP1, FOXA1, and FOXM1 may be used as potential biomarkers to predict the prognosis of patients with breast cancer. Functional enrichment indicated that FOX was mainly involved in cell division, cell senescence, cell cycle, and prolactin signaling pathway. In patients with breast cancer, FOXC2 expression was negatively correlated with the infiltration of B cells and positively correlated with the infiltration of neutrophils and dendritic cells. However, FOXM1 was negatively correlated with the infiltration of CD8 + T cells and macrophages and positively correlated with the infiltration of neutrophils and dendritic cells. These findings provided novel insights into the screening of prognostic biomarkers of the FOX family in breast cancer and laid a foundation for further research on the immune infiltration of the FOX transcription factor family members in tumors.