Shorter Disease-free Interval Research Articles

Hypoxia-associated markers in the prognosis of oral canine melanoma.

Canine oral malignant melanoma (COMM) is the most common neoplasm in the oral cavity characterized by local invasiveness and high metastatic potential. Hypoxia represents a crucial feature of the solid tumor microenvironment promoting cancer progression and drug resistance. Hypoxia-inducible factor-1α (HIF-1α) and its downstream effectors, vascular endothelial growth factor A (VEGF-A), glucose transporter isoform 1 (GLUT1), C-X-C chemokine receptor type 4 (CXCR4), and carbonic anhydrase IX (CAIX), are the main regulators of the adaptive response to low oxygen availability. The prognostic value of these markers was evaluated in 36 COMMs using immunohistochemistry. In addition, the effects of cobalt chloride-mediated hypoxia were evaluated in 1 primary COMM cell line. HIF-1α expression was observed in the nucleus, and this localization correlated with the presence or enhanced expression of HIF-1α-regulated genes at the protein level. Multivariate analysis revealed that in dogs given chondroitin sulfate proteoglycan-4 (CSPG4) DNA vaccine, COMMs expressing HIF-1α, VEGF-A, and CXCR4 were associated with shorter disease-free intervals (DFI) compared with tumors that were negative for these markers (P = .03), suggesting hypoxia can influence immunotherapy response. Western blotting showed that, under chemically induced hypoxia, COMM cells accumulate HIF-1α and smaller amounts of CAIX. HIF-1α induction and stabilization triggered by hypoxia was corroborated by immunofluorescence, showing its nuclear translocation. These findings reinforce the role of an hypoxic microenvironment in tumor progression and patient outcome in COMM, as previously established in several human and canine cancers. In addition, hypoxic markers may represent promising prognostic markers, highlighting opportunities for their use in therapeutic strategies for COMMs.

Innovative Surgical Approaches That Improve Individual Outcomes in Advanced Breast Cancer.

Breast cancer is the most common cause of cancer death in women and the second cause in the general population. The incidence has increased over time. Women in developing countries often present at an advanced stage where initial surgery is not feasible. Short disease-free intervals, the number of metastatic organs and liver metastasis were consistently associated with poor overall survival. Surgery is an integral part of the therapeutic plan for locally advanced breast cancer. The integration of surgical care into the management of patients with advanced cancer has changed substantially with the use of neoadjuvant chemotherapy. Also, more recently, neoadjuvant endocrine therapy and targeted therapies offer new opportunities to downsize the tumor burden and transform the role of surgery for this population from palliation to largely curative intent. Innovative surgical approach to the primary tumor in metastatic disease may provide survival benefits and local control in some patients. Similar to systemic therapy, surgical therapy for secondary dissemination should be considered in certain cases for improved individual outcomes. Advances in reconstructive techniques have improved the quality of life of these patients.

Long-term outcomes of SBRT for PSMA PET detected oligometastatic prostate cancer

BackgroundOligometastatic disease in prostate cancer (PCa) is a challenging clinical scenario encountered more frequently with the widespread adoption of PSMA-PET. SBRT aims to defer androgen deprivation and may deliver sustained biochemical failure (BF) free survival in selected patients. Little long-term data is currently available regarding the effectiveness of this approach.MethodsA retrospective single institution study of PSMA-PET directed SBRT without initial ADT for oligo-metachronous PCa. Median dose/fractionation was 24 Gy in 2# to bones and 30 Gy in 3# to lymph nodes. The primary endpoint was time to BF (PSA + 0.2 ug/L above nadir). Secondary endpoints included time to ADT for relapse (i.e. palliative ADT), BF defined as PSA nadir + 2 ug/L, toxicity, patterns of failure and survival. Patients were excluded if they received ADT with their SBRT, had short disease-free interval, or > 3 metastases on PSMA-PET.Results103 patients treated from November-2014 to December-2019 were analysed from our prospective database. Median follow-up was 5 years. 64 patients were treated for nodal only disease, 35 bone only and 4 mixed. 15% were free of any BF at 5 years with median time to BF of 1.1 years. 32% (33/103) of patients had further curative-intent radiation treatment following their first BF after SBRT, including subsequent SBRT. Eight patients underwent potentially curative treatment for their second or third relapse. Allowing for salvage treatment, 29/103 (28%) were biochemically disease free at last follow up. At 5 years, 39% of patients had never received any ADT and 55% had not started ADT for relapse with a median time to ADT for relapse of 5.5 years. There were 2 grade 3 toxicities (rib fracture and lymphoedema), and no local failures.ConclusionPSMA-PET guided SBRT for oligo-metachronous PCa recurrence in appropriately triaged patients results in excellent local control, low toxicity and over 50% ADT free at 5 years.

Treatment of loco-regional recurrence of nasopharyngeal carcinoma in a non-endemic area: oncologic outcomes, morbidity, and proposal of a prognostic nomogram.

The study assessed outcomes and toxicities of different treatment modalities for local and/or regional recurrent nasopharyngeal carcinoma (NPC) in a non-endemic area. Patients treated with curative intent for recurrent NPC with salvage surgery, photon-based radiotherapy, proton therapy (PT), with or without chemotherapy, at different Italian referral centers between 1998 and 2020 were included. Adverse events and complications were classified according to the Common Terminology Criteria for Adverse Events. Characteristics of the patients, tumors, treatments, and complications are presented along with uni- and multivariate analysis of prognostic factors. A survival predictive nomogram is also provided. A total of 140 patients treated from 1998 to 2020 were retrospectively assessed. Cases with lower age, comorbidity rate, stage, and shorter disease-free interval (DFI) preferentially underwent endoscopic surgery. More advanced cases underwent re-irradiation, fairly distributed between photon-based radiotherapy and PT. Age and DFI were independent factors influencing overall survival. No independent prognostic effect of treatment modality was observed. No significant difference in the morbidity profile of treatments was observed, with 40% of patients experiencing at least one adverse event classified as G3 or higher. Recurrent NPC in a non-endemic area has dissimilar aspects compared to its endemic counterpart, suggesting the need for further studies that can guide the choice of the best treatment modality.

A prediction model for distant metastasis after isolated locoregional recurrence of breast cancer

PurposeThe impact of progesterone receptor (PR) status on the prognosis of breast cancer after isolated locoregional recurrence (ILRR) remains unclear. This study evaluated the impact of clinicopathologic factors, including PR status of ILRR, on distant metastasis (DM) after ILRR.MethodsWe retrospectively identified 306 patients with ILRR diagnosed at the National Cancer Center Hospital between 1993 and 2021 from the database. Cox proportional hazards analysis was performed to examine factors associated with DM after ILRR. We developed a risk prediction model based on the number of detected risk factors and estimated survival curves using the Kaplan–Meier method.ResultsDuring a median follow-up time of 4.7 years after ILRR diagnosis, 86 patients developed DM, and 50 died. Multivariate analysis revealed that seven risk factors were associated with poor distant metastasis-free survival (DMFS): estrogen receptor-positive/PR-negative/human epidermal growth factor receptor 2-negative ILRR, short disease-free interval, recurrence site other than ipsilateral breast, no-resection of ILRR tumor, chemotherapy for the primary tumor, nodal stage in the primary tumor, and no endocrine therapy for ILRR. The predictive model classified patients into 4 groups based on the number of risk factors: low-, intermediate-, high-, and the highest-risk groups with 0 to 1, 2, 3 to 4, and 5 to 7 factors, respectively. This revealed significant variation in DMFS among the groups. A higher number of the risk factors was associated with poorer DMFS.ConclusionOur prediction model, which considered the ILRR receptor status, may contribute to the development of a treatment strategy for ILRR.

Should organs at risk (OARs) be prioritized over target volume coverage in stereotactic ablative radiotherapy (SABR) for oligometastases? a secondary analysis of the population-based phase II SABR-5 trial

Background and PurposeStereotactic ablative radiotherapy (SABR) for oligometastases may improve survival, however concerns about safety remain. To mitigate risk of toxicity, target coverage was sacrificed to prioritize organs-at-risk (OARs) during SABR planning in the population-based SABR-5 trial. This study evaluated the effect of this practice on dosimetry, local recurrence (LR), and progression-free survival (PFS). MethodsThis single-arm phase II trial included patients with up to 5 oligometastases between November 2016 and July 2020. Theprotocol-specified planning objective was to cover 95 % of the planning target volume (PTV) with 100 % of the prescribed dose, however PTV coverage was reduced as needed to meet OAR constraints. This trade-off was measured using the coverage compromise index (CCI), computed as minimum dose received by the hottest 99 % of the PTV (D99) divided by the prescription dose. Under-coverage was defined as CCI < 0.90. The potential association between CCI and outcomes was evaluated. Results549 lesions from 381 patients were assessed. Mean CCI was 0.88 (95 % confidence interval [CI], 0.86–0.89), and 196 (36 %) lesions were under-covered. The highest mean CCI (0.95; 95 %CI, 0.93–0.97) was in non-spine bone lesions (n = 116), while the lowest mean CCI (0.71; 95 % CI, 0.69–0.73) was in spine lesions (n = 104). On multivariable analysis, under-coverage did not predict for worse LR (HR 0.48, p = 0.37) or PFS (HR 1.24, p = 0.38). Largest lesion diameter, colorectal and ‘other’ (non-prostate, breast, or lung) primary predicted for worse LR. Largest lesion diameter, synchronous tumor treatment, short disease free interval, state of oligoprogression, initiation or change in systemic treatment, and a high PTV Dmax were significantly associated with PFS. ConclusionPTV under-coverage was not associated with worse LR or PFS in this large, population-based phase II trial. Combined with low toxicity rates, this study supports the practice of prioritizing OAR constraints during oligometastatic SABR planning.

Risk-adjusted hazard analysis of survival after pulmonary metastasectomy for uterine malignancies in 319 cases

ObjectiveThere is little evidence of the outcome of pulmonary metastasectomy for uterine tumors when comparing different histologies. This study aimed to delineate the primary histology that leads to more favorable outcomes after pulmonary metastasectomy. MethodsThe database of the Metastatic Lung Tumor Study Group of Japan for 1984 to 2016 was used to analyze the outcomes of patients with gynecologic malignancies who underwent pulmonary metastasectomy. Prognostic factors and long-term outcomes were compared according to the histology of the primary uterine tumors, specifically adenocarcinoma, squamous cell carcinoma, and sarcoma. The adjusted hazard risks according to disease-free intervals (DFIs) and the number and maximum size of resected tumors were also analyzed to delineate the pattern of risk trends. ResultsA total of 319 patients were included in the analysis (122 with adenocarcinomas, 113 with squamous cell carcinomas, 46 with sarcomas, and 38 with other types). The 5-year survival rate was 66.5% for the entire cohort, 71.6% for the patients with adenocarcinoma, 61.3% for those with squamous cell carcinoma, and 55.4% for those with sarcoma. Multivariate analyses identified the positive prognostic factors as DFI ≥12 months in adenocarcinoma and sarcoma and the primary site (corpus) of uterine tumors in adenocarcinoma. The nonlinear adjusted hazard risks indicated that a shorter DFI was associated with an elevated risk of death in patients with adenocarcinoma and sarcoma. ConclusionsThe survival outcome after pulmonary metastasectomy varies according to primary tumor histology, and the prognostic factors differ among histologic subtypes. Surgical indications should be determined based on the prognostic factors for each histology.

Preoperative Plasma miRNA Levels Predict Prognosis in Early-stage Malignant Melanoma.

Non-invasive circulating tumor biomarkers in liquid biopsy, such as microRNAs (miRNA), provide for better personalization of treatment strategies. The aim of our study was to assess the prognosis of patients with melanoma undergoing tumor resection with curative intent based on analysis of selected circulating miRNAs. A total of 22 patients with stage I to III melanoma were enrolled into this prospective study. Plasma samples were obtained pre-surgery and early post-surgery from peripheral blood draws. A panel of 23 candidate miRNAs was designed and expression of miRNAs were analyzed by reverse transcription-quantitative polymerase chain reaction with exogenous reference control cel-miR-39-3p. Higher preoperative expression levels of miR-99a (p=0.008), miR-320 (p=0.009), miR-1908 (p=0.001), miR-494 (p=0.018) and miR-4487 (p=0.048) were associated with a shorter disease-free interval. Similarly, higher preoperative plasma levels of miR-99a (p=0.017), miR-221 (p=0.026), miR-320 (p=0.016), miR-494 (p=0.009), miR-1260 (p=0.026) and miR-1908 (p=0.024) were associated with worse overall survival. No significant differences between pre- and postoperative plasma miRNA levels were observed. Liquid biopsy is a minimally-invasive approach which can lead to a better understanding of cancer behavior and offers the possibility of precise patient prognosis, allowing selection of the most appropriate treatment. Our study showed that preoperative plasma levels of miR-99a, miR-221, miR-320, miR-494, miR-1908 and miR-4487 were associated with disease-free interval and overall survival of patients with early-stage melanoma. This approach may help in decision-making about the appropriateness of modern adjuvant treatment administration in patients with resectable melanoma.

The Outcome of Discontinuing Tyrosine Kinase Inhibitors in Advanced Sarcoma Following a Favorable Tumor Response to Antiangiogenics Therapy.

(1) Background: The use of antiangiogenic TKIs (AA-TKIs) has recently emerged as a major paradigm shift in the treatment of advanced sarcoma. However, the feasibility of drug holidays for patients demonstrating a very favorable response remains unknown. (2) Methods: We aim to explore the outcomes of patients with advanced sarcoma who discontinued AA-TKIs after a (near-) complete remission or were long-term responders. Patients with advanced disease were included if they had bilateral or multiple lung metastases, extrapulmonary recurrence, a short disease-free interval, etc., at the initiation of AA-TKIs. (3) Results: A total of 22 patients with AA-TKI discontinuation were analyzed, with a median follow-up of 22.3 months post-discontinuation. Prior to discontinuation, there were four drug-induced complete remissions (CRs), twelve surgical CRs, and six long-term responders. Disease progression was observed in 17/22 (77.3%) patients, with a median of 4.2 months. However, since the majority were still sensitive to the original AA-TKIs and amenable to a second surgical remission, 7 out of these 17 patients achieved a second CR after disease progression and were thus considered as relapse-free post-discontinuation (pd-RFS). Therefore, the pd-RFS and post-discontinuation overall survival (pd-OS) in the last follow-up were 12/22 (54.5%) and 16/22 (72.7%), respectively. Remarkably, surgical CR and drug tapering off (versus abrupt stopping) were associated with a greater pd-RFS and pd-OS (p < 0.05). Furthermore, higher necrosis rates (p = 0.040) and lower neutrophil-to-lymphocyte ratios (NLR) (p = 0.060) before discontinuation tend to have a better pd-RFS. (4) Conclusions: Our results suggest that AA-TKI discontinuation with a taper-off strategy might be safe and feasible in highly selected patients with advanced sarcoma. Surgical CR, NLR, and tumor necrosis rates before discontinuation were potential biomarkers for AA-TKI withdrawal.

Blood Transfusion is Associated With Adverse Outcomes in Pediatric Solid Tumor Oncology Patients Following Tumor Resection.

Packed red blood cell (PRBC) transfusion is a lifesaving intervention that also has proinflammatory and immunosuppressive effects. Adults with a malignancy who receive PRBC transfusion have increased rates of infection, tumor recurrence, and decreased survival. The effect of PRBC transfusion among children with solid tumors is unknown. We performed a retrospective review of all children who underwent operative resection of a solid tumor malignancy. Data collected included demographic information, location of operation, nadir hemoglobin, and any PRBC transfusion within 30 days of tumor resection. Three hundred sixty children underwent tumor resection at our institution between 2002 and 2013; 194 (54%) received a perioperative blood transfusion. After adjusting for stage at diagnosis, tumor location, preoperative chemotherapy and nadir hemoglobin, blood transfusion was associated with a higher rate of postoperative infectious complications, shorter disease-free interval, and a higher rate of tumor recurrence. Each additional transfused unit increased the risk of postoperative infection (odds ratio 3.83; 95% confidence interval 1.21, 14.22, P =0.031). Among children with solid tumor malignancies, PRBC transfusion within 30 days of operation is associated with higher rates of postoperative infection. If transfusion becomes necessary, single unit increments should be transfused. Level III.

Outcomes after recurrence of low-grade endometrial stromal sarcoma (LGESS) (150)

Objectives: To evaluate clinical characteristics of patients with recurrent low-grade endometrial sarcoma (LGESS) and identify prognostic factors associated with improved outcomes. Methods: All patients with a diagnosis of recurrent LGESS treated for their first recurrence at our institution between 1980 and 2019 were retrospectively identified. All recurrent uterine pathologies were reviewed, and pertinent clinical data were abstracted from the medical record. Survival outcomes were estimated using Kaplan-Meier method and differences in survival were analyzed using Logrank tests. Results: Among 28 patients with recurrent LGESS, the median time to first recurrence after the initial diagnosis was 49.5 months (range: 5.1-265.5). The median age at the time of recurrence was 54 years (range: 26-83). The sites of first recurrence were abdomen/pelvis (20, 71%), lung only (7, 25%), lung/spine (1, 4%). Eighteen patients (65%) had multi-site recurrent disease. The median follow-up time was 75.9 months (range: 8.3-232.7). Twenty-two patients (79%) experienced subsequent recurrence(s) with median progression-free survival (PFS) of 34.3 months (95% CI: 14.5-54.2). Median overall survival (OS) after the first recurrence was 136.2 months (95% CI: 87.4-185.0). At the time of the first recurrence, 21 patients (75%) underwent secondary surgical cytoreduction (SSR), and seven (25%) received non-surgical management alone. Reasons for non-surgical management included bony involvement (n=2), diffuse metastatic disease (n=2), short disease-free interval (DFI) (n=1), local extent of disease (n=1), and patient declining resection (n=1). Of those who underwent SSR, complete gross resection (CGR) was obtained in 15 (71%). CGR was not associated with PFS or OS, as most subsequent recurrences were salvaged. Seventeen of 21 (81%) SSR patients received postoperative therapy. ER+ and PR+ recurrent tumors and single-site recurrent disease were factors associated with a significant improvement in PFS (p=0.005 and p=0.03, respectively), but these did not impact OS (p=0.5 and p=0.2, respectively). An initial DFI of >4 years was associated with improved PFS (p=0.06) but no improvement in OS (p=0.1). Conclusions: Patients with a first recurrence of LGESS are likely to recur again. Longer DFI, ER+/PR+ tumors and single-site disease are associated with greater time to subsequent recurrence. Outcomes are generally favorable with this rare tumor, and all multi-modality therapy options should be considered for salvage, including surgical resection. Objectives: To evaluate clinical characteristics of patients with recurrent low-grade endometrial sarcoma (LGESS) and identify prognostic factors associated with improved outcomes. Methods: All patients with a diagnosis of recurrent LGESS treated for their first recurrence at our institution between 1980 and 2019 were retrospectively identified. All recurrent uterine pathologies were reviewed, and pertinent clinical data were abstracted from the medical record. Survival outcomes were estimated using Kaplan-Meier method and differences in survival were analyzed using Logrank tests. Results: Among 28 patients with recurrent LGESS, the median time to first recurrence after the initial diagnosis was 49.5 months (range: 5.1-265.5). The median age at the time of recurrence was 54 years (range: 26-83). The sites of first recurrence were abdomen/pelvis (20, 71%), lung only (7, 25%), lung/spine (1, 4%). Eighteen patients (65%) had multi-site recurrent disease. The median follow-up time was 75.9 months (range: 8.3-232.7). Twenty-two patients (79%) experienced subsequent recurrence(s) with median progression-free survival (PFS) of 34.3 months (95% CI: 14.5-54.2). Median overall survival (OS) after the first recurrence was 136.2 months (95% CI: 87.4-185.0). At the time of the first recurrence, 21 patients (75%) underwent secondary surgical cytoreduction (SSR), and seven (25%) received non-surgical management alone. Reasons for non-surgical management included bony involvement (n=2), diffuse metastatic disease (n=2), short disease-free interval (DFI) (n=1), local extent of disease (n=1), and patient declining resection (n=1). Of those who underwent SSR, complete gross resection (CGR) was obtained in 15 (71%). CGR was not associated with PFS or OS, as most subsequent recurrences were salvaged. Seventeen of 21 (81%) SSR patients received postoperative therapy. ER+ and PR+ recurrent tumors and single-site recurrent disease were factors associated with a significant improvement in PFS (p=0.005 and p=0.03, respectively), but these did not impact OS (p=0.5 and p=0.2, respectively). An initial DFI of >4 years was associated with improved PFS (p=0.06) but no improvement in OS (p=0.1). Conclusions: Patients with a first recurrence of LGESS are likely to recur again. Longer DFI, ER+/PR+ tumors and single-site disease are associated with greater time to subsequent recurrence. Outcomes are generally favorable with this rare tumor, and all multi-modality therapy options should be considered for salvage, including surgical resection.

Long Non-Coding RNA RFPL3S Functions as a Biomarker of Prognostic and Immunotherapeutic Prediction in Testicular Germ Cell Tumor.

The incidence of testicular germ cell tumor (TGCT) is currently on the rise worldwide, of which 15%-30% of patients have occur recurrence and metastasis. However, clinical methods for diagnosing TGCT and judging its prognosis remained inadequate. In this study, we aimed to explore the possibility of testis-specific long-chain non-coding RNA (lncRNA) Ret finger protein-like 3S (RFPL3S) as a biomarker for TGCT diagnosis, prognosis, and treatment response by reviewing the TGCT gene expression data in Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. The cohort data and DNA methylation data of TGCT in TCGA were downloaded from TGCA, UCSC XENA, and GEO. The bioinformatic tools were used, including GEPIA2, Kaplan-Meier Plotter, LinkedOmics, UCSC XENA, Sangerbox Tools, GSCA, and Tumor Immune Dysfunction and Exclusion. Compared with normal testicular tissues, the RFPL3S expression was significantly reduced in TGCT, and was significantly negatively correlated with the patient’s Tumor, Node, Metastasis stage. Hypermethylation and low copy number of RFPL3S were present in TGCT, and low RFPL3S was associated with short disease-free and progression-free intervals. Silencing RFPL3S significantly enhanced the invasion ability and proliferation ability of TGCT cells as evaluated by Transwell and CCK-8 experiments. Additionally, RFPL3S expression was positively correlated with the infiltration of immune-activating cells such as B cells, CD8+ T cells, cytotoxic T cells, and natural killer cells, and negatively correlated with the infiltration of immunosuppressive cells such as Th17 and Th2. Higher RFPL3S expression was present in patients with immunotherapy benefits. In conclusion, we determined that the testis-specific lncRNA RFPL3S functioned as a tumor suppressor in TGCT and could be used as a prognostic predictor of TGCT, as well as a marker to predict the effect of TGCT immunotherapy.

Clinical Course and Predictors of Subsequent Recurrence and Survival of Patients With Ipsilateral Breast Tumor Recurrence.

PurposeTo evaluate the clinical course and long-term outcomes of patients with ipsilateral breast tumor recurrence (IBTR) after breast-conserving surgery (BCS) and identify independent prognostic factors for further recurrence.MethodsIn this retrospective study, we reviewed the records of 327 patients who experienced IBTR after undergoing BCS for breast cancer at Asan Medical Center during 1990–2013. Overall survival (OS) after IBTR and cumulative incidence rates of recurrences after IBTR were calculated. The association of clinicopathological factors with survival and the development of further recurrence after IBTR was determined in multivariate analysis.ResultsAt a median follow-up of 127.7 months, 97 patients experienced recurrence after IBTR. The 5-year and 10-year cumulative incidence rates of recurrence after IBTR were 32% and 41%, respectively. The 5-year and 10-year OS rates after IBTR were 86.6% and 70.3%, respectively. In multivariate analysis, hormone receptor negativity was associated with decreases in OS after IBTR (hazard ratio [HR] 2.83, 95% confidence interval [CI] 1.18–6.78). Patients with longer disease-free interval (DFI) had decreased risks of second recurrence (HR .99, 95% CI .99–1.00), and second locoregional recurrence (LRR) (HR .98, 95% CI .97–.99). Lymphovascular invasion (LVI) of IBTR was associated with increased recurrence rates (second recurrence-free survival, HR 3.58, 95% CI 2.16–5.94; second LRR free survival, HR 5.21, 95% CI 2.77–9.78; second distant metastasis-free survival, 2.11, 95% CI 1.04–4.30) and lower survival rates (OS after IBTR, HR 4.64, 95% CI 2.23–9.67).ConclusionsDespite subsequent recurrences during long-term follow-up, the survival rates after IBTR remained high. Patients with hormone receptor-negative tumors, shorter DFI, and tumors that present LVI of IBTR had higher risks for recurrence and poor survival rates after IBTR. The study findings may help in understanding the course and prognosis of IBTR patients and identifying high-risk IBTR to establish management strategies.

Abstract P1-18-09: Impact of prior adjuvant trastuzumab (aT) on clinical characteristics, patterns of recurrence and outcomes in 4145 patients with Her2 positive (HER2+) metastatic breast cancer (MBC)- Results from the French ESME UNICANCER program

Abstract Background: The management of HER2+ BC has changed dramatically with the introduction and widespread use of HER2-targeted therapies, especially in the adjuvant setting. It is well-known that de novo metastatic HER2+ breast cancer patients have better outcomes that women with metastatic relapse. This could be related both to a lead time bias, as well as to an ATRESS (adjuvant therapy-related shortening of survival) phenomenon [1]. Indeed, cancer treatments induce increased both clonal selection, as well as globally tumor resistance and agressivity [2]. However, there is relatively limited real-world information on the impact of adjuvant and neoadjuvant anti-HER2 targeted treatments on patterns of recurrence and outcomes of HER2+ MBC. Thus, the purpose of this study was to determine how and how long anti-HER2 targeted treatment in early setting impact outcomes of patients with HER2+ recurring BC. Methods: Since 2014, the 18 French Cancer Centers launched the Epidemiological Strategy and Medical Economics (ESME) program to provide real-world data on MBC patients (pts). All pts who started a 1st-line treatment for MBC between 01-Jan-2008 and 31-Dec-2017 were included. We examined clinical characteristics and outcomes (overall survival [OS] and time to 1st metastasis [TTM]) in patients with HER2+ MBC pretreated with trastuzumab in the (neo)adjuvant setting (aT) compared with trastuzumab-naïve patients and patients with de novo HER2+ MBC. Multivariate analyses adjusted for baseline demographic, prognostic factors, adjuvant treatment received and time to MBC. Results: Among the 23698 pts of the ESME database, 4145 were women treated in 1st line of a HER2+ MBC: 1716 pts (41%) had de novo and 2429 pts (59%) recurrent and 65% had Hormone Receptor (HR) + MBC; 53%, 26% and 21% had respectively 1, 2, or &amp;gt; 2 metastatic sites (64% visceral and 11% brain). With a median follow-up of 60.7 m, median OS is 42.4 m (95% CI: 40.1-45.0) for patients who relapsed. OS is significantly longer in de novo MBC: 64.7 m (95% CI: 60.2-73) (HRadjusted=0.68, 95% CI: 0.62-0.76, p &amp;lt; 0.0001). Among pts with recurrent MBC, 56% (1343) had received adjuvant trastuzumab (aT). As 1st-line therapy for MBC, 86 % of pts received HER2-targeted agents (74% T-based, 24% T-pertuzumab-based). Median TTM was 46.9 months (m): 57.6 m in HR+ and 30.2 m in HR-. Among pts with HR- diseases, 38% relapsed during the first 2 years of follow-up and 30% after 4 years (14.8%% and 56.9% in HR+ respectively). Among pts with recurrent MBC, crude median OS is inferior in pts who received aT, as compared to those who did not: 37.2 m (95% CI: 34.4-40.3) vs. 53.5 m (95% CI: 47.6-60.1), but this difference does not persist after adjustment for age, performans status, disease-free interval and number and type of metastatic sites in the multivariate model (HR=1.05, 95% CI: 0.91-1.22). A short disease-free interval (6-24 months compared to &amp;gt;48) remains, however, a strong adverse prognostic factor (HR=2.1, 95% CI: 1.82-2.50). Conclusions: The receipt of adjuvant trastuzumab does not predict for worse outcomes when adjusted to the other prognostic factors, among patients who relapsed during the 2008-2017 period. An ATRESS phenomenon is not suggested, although we cannot rule it out for those who relapsed within the initial 2 years. The much better prognosis of de novo MBC may be largely linked to lead time biases. Citation Format: Fanny Le Du, Matthieu Carton, Mahasti Saghatchian, David Perol, Barbara Pistilli, Etienne Brain, Delphine Loirat, Laurence Vanlemmens, Thomas Vermeulin, Christelle Levy, Anthony Goncalves, Mony Ung, Marie Robert, Anne Jaffre, Mathieu Robain, Suzette Delaloge, Véronique Dieras. Impact of prior adjuvant trastuzumab (aT) on clinical characteristics, patterns of recurrence and outcomes in 4145 patients with Her2 positive (HER2+) metastatic breast cancer (MBC)- Results from the French ESME UNICANCER program [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-18-09.

Baseline prognostic factors affecting survival in recurrent and/or metastatic salivary gland adenoid cystic carcinoma

ObjectivesAdenoid cystic carcinoma (AdCC) is a rare disease, with indolent behavior and poor long-term survival. Many studies have evaluated the role of clinical and pathological factors at presentation on the risk of recurrence. In this study we investigated whether baseline demographic, clinical, and pathological characteristics at the time of primary curative treatment could influence the prognosis of patients once local and/or distant recurrence occurred. MethodsAll patients affected by primary salivary gland AdCC and treated with curative surgery from January 1997 to June 2016 were reviewed, evaluating those who later developed loco-regional recurrence and/or distant metastasis. Time from the first relapse to death (recurrent/metastatic overall survival, RMOS) was considered the outcome of interest. ResultsOut of 87 surgically treated AdCC patients, 36 relapsing lesions were included. Median ages at first presentation and recurrence were 55 and 60-year-old, respectively; 58% were females. Median disease-free-interval (DFI) was 22.0 months. Five-year RMOS was 47%. At univariate analysis, age ≥ 60-year-old (HR:2.67, p = 0.030), primary tumor lympho-vascular invasion (LVI) (HR:5.38, p = 0.003), adjuvant radiotherapy (RT) in the primary setting (HR:0.37, p = 0.043), and DFI < 30 months (HR:3.94, p = 0.008) significantly affected RMOS. Multivariable analysis confirmed the presence of LVI and shorter DFI as independent risk factors. ConclusionsKnowledge of baseline clinicopathological features is helpful in the prognostic stratification of patients with recurrent AdCC, with LVI as the most relevant baseline factor. Adjuvant RT demonstrated its protective role on survival even once recurrence occurred, further supporting its adoption in the primary setting.

Outcomes After Curative Metastasectomy for Patients with Malignant Melanoma: A Systematic Review and Meta-analysis.

Evidence on the role of curative metastasectomy (CM) for malignant melanoma (MM) patients is limited, especially in the current era of effective systemic therapy. A systematic review and meta-analysis were performed to ascertain the role of CM compared with incomplete or nonsurgical treatment for patients with MM. Medline, Embase, and Scopus databases were searched for studies investigating CM for MM until 30 September 2021. The review included studies that compared CM with no-CM and reported a hazard ratio (HR) after multivariate analysis for overall survival. A random-effects model with inverse variance was used to calculate pooled HR. The Newcastle-Ottawa Scale was used to assess the risk of bias. For the final analysis, 40 studies including 31,282 patients (CM, 9958; no-CM, 21,324) were considered. Compared with no-CM, CM was associated with a significantly lower risk of death (HR, 0.42; 95% confidence interval [CI], 0.38-0.47; p < 0.00001). Subgroup analysis showed that the outcome was independent of the effective systemic therapy and anatomic location of metastasis. An unfavorable prognosis was associated with advancing age, elevated lactate dehydrogenase (LDH), male gender, prior stage 3 disease, multiple metastases and organ sites, and shorter disease-free interval. Curative metastasectomy for MM is associated with a lower risk of death than non-curative treatment methods. Selection bias and underlying weakness of studies reduced the strength of evidence in this review. However, CM should be a part of the multimodality treatment of MM whenever technically feasible.

Salvage Surgery in Recurrent Oral Squamous Cell Carcinoma.

More than half of patients with oral cancer recur even after multimodality treatment and recurrent oral cancers carry a poorer prognosis when compared to other sites of head and neck. The best survival outcome in a recurrent setting is achieved by salvage surgery; however, objective criteria to select an ideal candidate for salvage surgery is difficult to frame, as the outcome depends on various treatment-, tumor-, and patient-related factors. The following is summarizes various tumor- and treatment-related factors that guide our decision-making to optimize oncologic and functional outcomes in surgical salvage for recurrent oral cancers. Short disease-free interval, advanced tumor stage (recurrent and primary), extracapsular spread and positive tumor margins in a recurrent tumor, regional recurrence, and multimodality treatment of primary tumor all portend worse outcomes after surgical salvage. Quality of life after surgical intervention has shown improvement over 1 year with a drastic drop in pain scores. Various trials are underway evaluating the combination of immunotherapy and surgical salvage in recurrent head and neck tumors, including oral cavity, which may widen our indications for salvage surgery with improved survival and preserved organ function.

PTEN promoter methylation predicts 10-year prognosis in hormone receptor-positive early breast cancer patients who received adjuvant tamoxifen endocrine therapy

PurposeThere remain a lack of biomarkers for endocrine therapy resistance in patients with breast cancer (BC), which is proving to be a great challenge. In vitro experiments have shown that downregulation of PTEN expression leads to resistance to tamoxifen (TAM) in BC cells. We aimed to investigate the predictive role of tumor PTEN promoter methylation and PTEN expression in long-term survival after TAM adjuvant therapy in patients with early-stage BC.MethodsFrom 2001 to 2013, 105 patients with stage I–III BC who were treated with standardized adjuvant TAM for 5 years or until relapse in West China Hospital (WCH) were enrolled in this study. PTEN expression and DNA methylation of three specified sequences from the PTEN promoter in primary tumors were measured using immunohistochemistry and pyrosequencing. A cohort of 159 hormone receptor-positive patients receiving TAM treatment from The Cancer Genome Atlas (TCGA) database was used for verification.ResultsMedian follow-up time for the WCH cohort was 141.7 months. The low, moderate, and high PTEN expression groups had differing 10-year disease-free survival (DFS) (42.3%, 55%, 81%, respectively, P = 0.027) and overall survival (OS) rates (65%, 84.2%, 90.5%, respectively, P = 0.027). Higher methylation levels of the second sequence (− 819 to − 787 bp), rather than the first (− 1143 to − 1107 bp) or third sequence (− 663 to − 593 bp), independently increased the risk of disease recurrence (hazard ratio = 2.60) and death (hazard ratio = 3.79) in the WCH cohort, according to multivariate Cox regression analysis. Importantly, out of the five CpG islands located within this sequence, only high methylation of the − 796 CpG island predicted shorter DFS and OS. In TCGA validation cohort, there was also a trend of higher methylation of the − 796 CpG island correlating with shorter disease-free intervals, with borderline significance (P = 0.057).ConclusionLow PTEN expression and high methylation of its promoter (sequence − 819 to − 787 bp) in tissue predict poor DFS and OS in hormone receptor-positive early BC patients who received adjuvant TAM.

Oncologic outcomes according to the level of disease burden in patients with metachronous distant metastases from uterine cervical cancer: a Korean Radiation Oncology Group study (KROG 18-10).

ObjectiveThis study aimed to evaluate the oncologic outcomes according to disease burden in uterine cervical cancer patients with metachronous distant metastases.MethodsBetween 2005 and 2015, 163 patients with metachronous distant metastases from uterine cervical cancer after receiving a definitive therapy were evaluated at seven institutions in Korea. Low metastatic burden was defined as less than 5 metastatic sites, whereas high metastatic burden was others. Each metastasis site was divided based on the lymph node (LN) and organs affected. The overall survival (OS) and progression-free survival (PFS) were assessed. Cox proportional hazards models, including other clinical variables, were used to evaluate the survival outcomes.ResultsThe median follow-up duration was 22.2 months (range: 0.3–174.8 months). Para-aortic LNs (56.4%), lungs (26.4%), supraclavicular LNs (18.4%), and peritoneum (13.5%) were found to be the common metastasis sites. Among 37 patients with a single metastasis, 17 (45.9%) had LN metastases and 20 (54.1%) had organ metastases. The 1- and 2-year OS rates were 73.9% and 55.0%, respectively, whereas the PFS rates were 67.2% and 42.9%, respectively. SCC Ag after recurrence and high metastatic burden were significant factors affecting the OS (p=0.004 and p<0.001, respectively). Distant organ recurrence, short disease-free interval (≤2 years), and high metastatic burden were unfavorable factors for PFS (p=0.003, p=0.011, and p=0.002, respectively).ConclusionA favorable oncologic outcome can be expected by performing salvage treatments in selected patients with a long disease-free interval, low metastatic burden, and/or lymphatic-only metastasis.

Clinical outcome and prognostic factors in recurrent oral squamous cell carcinoma after primary surgical treatment: a retrospective study

ObjectivesSurvival for patients with recurrent oral squamous cell carcinoma is usually poor, and the most effective treatment has not yet been clearly defined. The present study evaluates the outcome in radiotherapy-naïve patients after recurrence of oral squamous cell carcinoma with respect to different treatment modalities including surgery, radiation, chemoradiation, and palliative treatment.Patients and methodsIn this retrospective study, we included all patients with primary oral squamous cell carcinoma who received exclusively surgical therapy between 2010 and 2020 and who suffered from locoregional recurrence in their follow-up. Patients with previous adjuvant therapy were excluded from this protocol. Clinical and pathological parameters were collected and statistically evaluated. Survival analysis was performed according to Kaplan–Meier. The primary endpoints were overall and progression-free survival in dependance of treatment strategy for recurrent tumors.ResultsOut of a total of 538 patients with surgically treated primary oral squamous cell carcinoma, 76 patients met the inclusion criteria. The mean follow-up was 38 ± 32 months. Patients who received surgically based therapy had a significantly better outcome in terms of disease-free survival (DFS) and overall survival (OS) (DFS p < 0.001; OS p < 0.001). The presence of regional metastases and a short disease-free interval (DFI) between primary and recurrent cancer were significant predictors for adverse outcomes (DFI p < 0.001).ConclusionWe recommend primary surgical therapy for radiotherapy-naïve patients with recurrent oral squamous cell carcinoma, supplemented by risk-adapted adjuvant therapy.Clinical relevanceSurgical therapy continues to play a central role in the treatment of radiotherapy-naïve patients with recurrent oral squamous cell carcinoma.