Longer OS Research Articles

Relationship between clinical efficacy and AEs of IMCgp100, a novel bispecific TCR–anti-CD3, in patients with advanced melanoma.

9530 Background: Bispecific antibodies have shown activity in hematologic (heme) but not solid tumors. ImmTAC molecules are unique TCR–anti-CD3 bispecifics that redirect T cells against intracellular antigens. IMCgp100, an ImmTAC targeted against melanocyte-associated lineage antigen gp100, has shown monotherapy responses in advanced melanoma with associated immune changes. IMCgp100 causes rash and cytokine-mediated AEs, hypothesized to be on-target (gp100) or effector (CD3) mediated. We explored clinical and biological characteristics of pts associated with treatment benefit. Methods: 84 HLA-A2 positive advanced melanoma pts received IMCgp100 on study IMCgp100-01 in 13 dose escalation cohorts. Efficacy was assessed by Kaplan–Meier survival and treatment related AEs (TRAE) reported by CTCAE v4.0. Serum samples evaluated changes in cytokines. A multivariate analysis investigated the relationship between efficacy and safety variables. Results: Demographics: 73% cutaneous (CM), 23% uveal (UM) primaries; 51% LDH > ULN; 25% received prior anti-PD(L)1. 83 (99%) pts had ≥1 TRAE; most commonly in skin (rash 82%, pruritus 69%) or cytokine-mediated (pyrexia 57%); the majority were Grade 1–2 and occurred and resolved within first 3 doses. The 2 most frequent Grade ≥3 TRAEs were rash (26%) and lymphopenia (13%). IMCgp100 induced transient increases in peripheral cytokines (peaking Day 1–2) that attenuated with subsequent doses; cytokine-mediated AE had similar kinetics.1-yr OS was 65% (95% CI: 48–78). In multivariate analysis, longer OS was associated with: LDH ≤ULN (p = 0.002) and any-grade rash occurring within 21 days (p = 0.003); melanoma primary site and prior anti-PD-(L)1 did not significantly affect outcome. In exploratory analyses, longer OS associated with lower baseline serum IL-6 (n = 43) or TNFα (n = 44). Conclusions: IMCgp100 is a first-in-class, TCR-based bispecific with monotherapy efficacy in advanced melanoma. AEs were manageable and consistent with MoA. Association between IMCgp100 efficacy and on-target TRAEs, previously reported for bispecifics to heme lineage antigens, is now recognized for solid tumor lineage antigens. Pivotal studies in UM are ongoing. Clinical trial information: NCT01211262.

Correlation betwen MKK4 expression (exp) and clinicopathological features, KRAS/NRAS mutation in metastatic colorectal cancer (mCRC).

e14500 Background: We aimed to evaluate correlation between MKK4 exp & clinicopathological features in mCRC Methods: MKK4 exp was assessed by immunoreactive score (IRS). Staining intensity [0 (no), 1+ (weak), 2+ (moderate), 3+ (strong)] & % of positively stained cells [0 (0%), 1( < 10%), 2 (11-50%), 3 (51-80%), 4 ( > 80%)]. IRS was calculated by this formula (IRS = SI × PP). Cut-offs were explored with ROC analysis. AUC was 0.629 (95%CI:0.419-0.840) & best cut-off value for MKK4 was 2.5 (sensitivity of 68 %). Groups were WIR ('weak'; IRS:0-2) & SIR ('strong'; IRS ≥3). Results: We enrolled 95 patients. Median follow-up was 31.4 months. MKK4 exp strength outcomes are shown in table. K-ras/N-ras mutation rate was 45.2%. WIR patients had longer OS (p: 0.03). In WIR group, metastatic ones at diagnosis had shorter DFS (p:0,05). There was no PFS difference (p: 0,15). In correlation analysis, there was a a negative correlation between MKK4 expression & 1st line treatment resistance, k-ras/n-ras mt, OS, PFS, DFS (r: -0.01; r: -0,06; -0,02; -0,10; -0,06; -0,34) ( p:0,04 for DFS). Conclusions: MKK4 exp inversely correlates with survival outcomes & ras mutation. WIR leads longer DFS & OS. [Table: see text]

Associations of insulin-like growth factor binding proteins and adiponectin with disease progression and mortality in metastatic colorectal cancer: Results from CALGB/SWOG 80405 (Alliance).

3035 Background: Energy balance-associated biomarkers such as insulin-like growth factors (IGFs) and IGF-binding proteins (IGFBPs) have been associated with risk and prognosis of various malignancies. Their relationship to disease progression and mortality in metastatic colorectal cancer (mCRC) requires further study. Methods: In a prospective cohort study, baseline plasma IGFBP-3, IGFBP-7, C-peptide, IGF-I, and adiponectin were measured at trial registration among 1,086 patients participating in a National Cancer Institute-sponsored clinical trial of first-line therapy for mCRC. We used Cox proportional hazards regression to adjust for confounders and examine associations of biomarkers with overall (OS) and progression-free survival (PFS). Results: Higher plasma IGFBP-3 was associated with longer OS (adjusted Ptrend < .001) and PFS (adjusted Ptrend = .003). Compared to patients in the lowest IGFBP-3 quintile, patients in the highest quintile experienced an adjusted HR for all-cause mortality of 0.58 (95% CI 0.42 to 0.78) and for disease progression or mortality of 0.60 (95% CI 0.45 to 0.82). Higher plasma IGFBP-7 was associated with shorter OS (adjusted Ptrend < .001) and PFS (adjusted Ptrend = .02). Compared to patients in the lowest IGFBP-7 quintile, patients in the highest quintile experienced an adjusted HR for all-cause mortality of 1.52 (95% CI 1.24 to 1.88) and for disease progression or mortality of 1.28 (95% CI 1.05 to 1.57). C-peptide and IGF-I were not significantly associated with patient outcomes (adjusted Ptrend = .73 and .30 for OS). Adiponectin was not associated with OS; there was a U shaped association between adiponectin and PFS, wherein low and high values were associated with shorter PFS ( Pnon-linear trend = .03). Conclusions: In patients with mCRC, high plasma IGFBP-3 and low IGFBP-7 were associated with reduced risk of disease progression and mortality. These data suggest that energy-balance associated biomarkers may offer prognostic and biologic insights into mCRC. Support: U10CA180821, U10CA180882, BMS, Genentech, Pfizer, Sanofi; https://acknowledgments.alliancefound.org .

Efficacy of retreatment with anti-EGFRs in mCRC is not predictable by clinical factors related to prior lines of therapy: A multi-institutional analysis.

3540 Background: Retrospective analyses and phase 2 studies suggest that administering an anti-EGFR in advanced lines may be effective in mCRC pts who achieved benefit from a 1st-line anti-EGFR containing regimen. The identification of clinical features associated with benefit from anti-EGFR re-treatment (re-tx) in pts experiencing PD during 1st-line anti-EGFR (rechallenge) or after its interruption (reintroduction), is a major clinical need. Methods: A real-life data-base including a total of 5530 pts treated at 6 insitutions from December 2010 to October 2018 was queried. Pts retreated with anti-EGFRs, with RAS/ BRAF wild-type status on tissue samples, who had received a 1st-line anti-EGFR-based tx with at least SD as best response, and at least one further line of therapy before anti-EGFR re-tx, were included. The association with RECIST response (RR), PFS and OS was investigated for the following variables: RR (PR or CR vs SD) and PFS during 1st-line; time from the last anti-EGFR administration to 1st-line PD (i.e. re-introduction vs rechallenge); reason for anti-EGFR discontinuation in 1st-line (PD vs. other); number of anti-EGFR-free lines of therapy before re-tx; anti-EGFR free interval (time between the last anti-EGFR administration in 1st-line and the time of re-tx); primary tumor side; time from the diagnosis of metastatic disease to re-tx (≥ vs. < 18 mos). Results: Data from 86 patients were retrieved, 56 (65%) and 30 (35%) received anti-EGFR rechallenge or reintroduction, respectively. Median anti-EGFR free interval was 15.1 mos. The RR during re-tx was 19.8%, with a DCR of 46.5%. Median PFS and OS were 3.6 and 10.2 mos, respectively. No significant association of investigated features with RR and PFS was observed. No differences in RR or PFS were observed among patients receiving anti-EGFR re-tx as rechallenge or reintroduction (20.4% vs 23.1%, p = 0.99; median PFS: 3.49 vs 4.97 mos, p = 0.61). Patients with left-sided tumors had longer OS (HR: 0.50, 95%CI: 0.26-0.93, p = 0.005). Conclusions: Clinical factors that are generally believed to affect the efficacy of anti-EGFR re-tx are not confirmed in our series. Therefore, clinicians should not rely on those characteristics in their decision-making on anti-EGFR re-tx, and adequate studies for implementing liquid biopsy in clinical practice are urgently needed.

Clinical implications of hyperprogression with immune checkpoint inhibitors in patients with head and neck squamous cell carcinoma (HNSCC).

6034 Background: Hyperprogressive disease (HPD) refers to paradoxical acceleration of tumor growth kinetics (TGK) after initiation of treatment with anti- PD-1/PD- L1 agents and has been reported across tumor types in 4-29% of patients using different definitions. Preliminary data suggest that HPD might affect response to subsequent therapies. Methods: We compared TGK prior and TGK upon immunotherapy (IO) in 62 patients (pts) with recurrent/metastatic (R/M) HNSCC treated with PD-1/PD-L1 inhibitors. The TGK ratio (TGKR, ratio of tumor growth velocity before and upon treatment) was calculated. The first imaging assessment was performed 3 months (mo) after IO initiation. HPD was defined as 1. Radiological HPD (TGKR≥2) or 2. Clinical HPD (Disease-related rapid clinical deterioration post IO). Results: After median follow-up of 12.3 mo (range, 0.4-28.1), 43 pts progressed and 38 died. Median PFS was 2.8 mo (95%CI, 2.2-3.4) and median OS 8.6 mo (95%CI, 4.2-12.9). HPD was observed in 16 pts (25.8%), while 15 pts had early PD (Time to Treatment failure, TTF < 3 mo) and 31 late PD (TTF > 3mo). Among 16 pts with HPD, 11 had radiological HPD and 10 had clinical HPD. 4 pts had both clinical and radiological HPD. Pts with late PD had median OS 11.3 mo (95%CI, 9.3-13.3), those with early PD 5.2 mo (95%CI, 3.1-7.3 months) and those with HPD 5.1 mo (95%CI, 4.4-5.9) (p < 0.005). Regarding post-progression OS, pts with late PD had median 11.3 mo (95%CI 0-22.8), those with early PD 2.5 mo (95%CI 0.6-4.4) and those with HPD 4.2 mo (95%CI 1.7-6.7) (p = 0.001). Pts with HPD had a trend for longer median post-progression OS compared to pts with early PD (p = 0.121). Median PFS with chemotherapy after immunotherapy failure was 3.0 mo (95%CI 2.4-3.6) for pts with late PD, 2.1 mo (95%CI 0.9-3.4) for pts with early PD and 6.1 mo (95%CI 3.0-9.3) for those with HPD (p = 0.040). HPD was associated with longer median PFS with chemotherapy compared to pts with early PD (p = 0.016), while the difference in median PFS with chemotherapy between pts with HPD and late progressors was non-statistically significant (p = 0.260). Conclusions: Radiological or clinical HPD was observed in 25.8% of patients with R/M HNSCC treated with IO. Early progression to immunotherapy is an important predictor of short survival, while HPD was associated with improved PFS to subsequent chemotherapy.

Chemotherapy combined with antiangiogenesis drugs in stage IV sarcoma patients: Efficacy data from the largest cohort study from China.

e22505 Background: Chemotherapy agents such as doxorubicin are not curative and new therapies for metastatic sarcomas are urgently needed. Several anti-angiogenesis therapeutic drugs such as Apatinib and Endostar have been widely used as monotherapy or combined treatments. We performed a retrospective study with the largest Chinese sarcoma cohort to investigate the efficacy of different anti-angiogenesis strategies. Methods: Data of NCT03121833 and NCT03121846 were collected. The information of 119 sarcoma patients in stage IV treated in Tianjin Medical University Cancer Hospital from Oct. 2009 to Aug. 2018 was collected. These sarcoma patients received chemotherapy, anti-angiogenesis therapies, or combined treatments. Chemotherapy was administered with single-agent Adriamycin or combination regimens according to NCCN guideline. Endostar was given at a dose of 15mg once daily by intravenous infusion for 14 days combined with chemotherapy regimens. Apatinib were given at a starting dose of 500 mg daily. Efficacy was evaluated according to RECIST1.1. Treatment-related adverse effects (AEs) were also evaluated. Results: 119 patients (46 bone sarcomas and 73 soft tissue sarcomas) were enrolled into four groups according to different treatment strategies (Table). The ORR had no significantly difference but DCR was significantly different, with the highest rate in chemotherapy plus apatinib group. The mPFS and mOS had no significantly difference. All the AEs were manageable. Conclusions: Chemotherapy combined with anti-angiogenesis drugs such as Apatinib and Endostar significantly increase the response rate. Apatinib is effective and well tolerated for advanced sarcoma patients. As for Apatinib treatment, the patients who suffered hypertension, hand-foot-skin reaction or proteinuria have significant longer OS than those without these AEs, which is first report in sarcoma patients. Clinical trial information: NCT03121833; NCT03121846. [Table: see text]

Effect of patient age on efficacy of FOLFIRI plus cetuximab vs bevacizumab in 1st-line treatment of metastatic colorectal cancer: An analysis of FIRE-3 (AIO KRK 0306).

3541 Background: FIRE-3 compared 1st-line therapy with FOLFIRI plus either cetuximab or bevacizumab in 592 KRAS exon 2 wt mCRC patients. The subgroup of extended RASwt patients consisted of 400 patients. The median age of patients treated in FIRE-3 was 64 years. Analyses of efficacy of doublet-chemotherapy in patients >70 years have shown inconsistent results. Methods: In this exploratory analysis, patients were grouped into cohorts with 65 years and 70 years as a cut-off for age-related analysis of the FIRE-3 study population. ORR was compared using Fisher´s exact test, Survival analyses were done using Kaplan-Meier estimation and median survival times were compared using log-rank testing. Results: Within the RAS wt population, patients older than 70 years had a significantly shorter OS when compared to patients ≤70 years of age in both arms (p= 0.02 for cetuximab arm, p= 0.02 for bevacizumab arm). Patients ≤65 years and ≤70 years had a significantly longer OS when treated with FOLFIRI plus cetuximab compared to FOLFIRI plus bevacizumab (p= 0.01 and 0.02 respectively). The OS benefit of cetuximab treated patients compared to bevacizumab treated patients was consistent for patients ≤65 years (p=0.005) and patients ≤70 years (p= 0.009) of age. In patients older than 70 years, however, comparable efficacy of bevacizumab and cetuximab was observed. This effect of age on outcome appears to be affected by sidedness. RAS wt population (n=400). Conclusions: In the overall RAS wt population, younger patients have a significant OS benefit when treated with FOLFIRI plus cetuximab compared to FOLFIRI plus bevacizumab, while this was not the case in patients older than 70 years.[Table: see text]

High expression of miR-338 is associated with poor prognosis in acute myeloid leukemia undergoing chemotherapy.

Acute myeloid leukemia (AML) is a heterogeneous disease with unfavorable outcomes. MicroRNAs (miRNAs) are important regulators and prognostic factors involved in AML. To determine the clinical role of miR-338 in AML, a total of 164 adults with de novo AML were collected. These patients were classified into a chemotherapy group and an allogeneic hematopoietic stem cell transplantation (allo-HSCT) group according to the clinical treatment, and then each group was divided into two subgroups based on the median miR-338 expression values. We found that upregulated miR-338 positively correlates with higher frequencies of complex karyotype, RUNX1 mutation, and poor risk status. In the chemotherapy group, high expression of miR-338 was independently associated with shorter EFS and OS. However, no significant differences were observed between the two subgroups within the allo-HSCT group. We also divided all patients into two groups according to the median miR-338 expression values of the whole cohort. In the miR-338 high expression group, patients receiving allo-HSCT had longer OS and EFS than those receiving chemotherapy only. In contrast, patients receiving different therapies had similar OS and EFS in the miR-338 low expression group. Our study suggests that high expression of miR-338 is an adverse prognostic biomarker in patients with AML undergoing chemotherapy and may guide treatment decisions for AML. Furthermore, allo-HSCT could significantly overcome the negative effect of high miR-338 expression, but it seemed to be unbeneficial and unnecessary for low miR-338 expressions.

Outcomes of concurrent chemoradiotherapy versus chemotherapy alone for esophageal squamous cell cancer patients presenting with oligometastases.

The potential survival benefits of adding radiotherapy to systemic therapy for esophageal cancer patients with oligometastases are unknown. In this retrospective analysis, patients with stage IV esophageal cancer (according to the American Joint Committee on Cancer Seventh edition staging system) with ≤3 metastases who underwent chemotherapy with cisplatin/paclitaxel between 2012 and 2015 were identified. Patients received chemotherapy (CT) alone vs. concurrent chemoradiotherapy (CCRT) to all metastases. Of 461 patients, 97% had squamous cell cancer. One hundred and ninety-six patients (42.5%) received CCRT and 265 (57.5%) underwent CT alone. At week 8, there were 3 (1.5%) complete responses (CR) and 95 (48.5%) partial responses (PR) in the CCRT group, compared to 3 (1.1%) CR and 102 (38.5%) PR in the CT alone group. The overall rate of improvement in dysphagia score was noted in 78.5% of patients in the CCRT group versus 61.5% in the CT alone group (P=0.014). A statistically significant difference was demonstrated in disease control rate between the two groups (81.6% vs. 64.5%, P<0.001). Patients who underwent CCRT had superior median PFS and a trend toward longer median OS compared to those receiving CT alone (8.7 vs. 7.3 months, P=0.002 and 16.8 vs. 14.8 months, P=0.056, respectively). The median OS was 19.3 months in patients who achieved CR/PR, compared to 14.9 months and 9.6 months for patients who had stable disease and progressive disease, respectively (P<0.001). Compared to chemotherapy alone, chemoradiation to all sites in patients with esophageal cancer with ≤3 metastases may lead to a modest increase in PFS and a trend toward longer OS. Further investigation of optimal integration of radiotherapy and chemotherapy in these patients is warranted.

Assessment of potential predictive value of peripheral blood inflammatory indexes in 26 cases with soft tissue sarcoma treated by pazopanib: a retrospective study.

PurposeThe aim of this study was to evaluate the prognostic and predictive value of neutrophil-to-lymphocyte ratio (NLR), derived neutrophil-to-lymphocyte ratio (DNLR), lymphocyte-to-monocyte ratio (LMR), and platelet-to-lymphocyte ratio (PLR) in soft tissue sarcoma (STS) cases treated with pazopanib.Materials and methodsThe study population included 26 STS cases treated with pazopanib for at least 3 months. NLR, DNLR, LMR, and PLR were evaluated at baseline, and at third month of therapy and also compared with response to pazopanib. Median measurements were taken as cutoff for NLR (4.8), DNLR (3.1), LMR (3.6), and PLR (195). The associations between these cutoff values and survival times (progression-free survival [PFS] and overall survival [OS]) were assessed by Kaplan–Meier curves and Cox proportional models.ResultsPatients with low pretreatment NLR and DNLR had longer OS (P=0.022, P=0.018), but low PLR was found to be associated only with longer OS. Additionally, decrease in NLR and DNLR after 3 months of therapy as compared with pretreatment measurements was found to be associated with an advantage for OS (P=0.021, P=0.010, respectively) and PFS (P=0.005, P=0.001, respectively). Response to pazopanib; changes in NLR, DNLR, LMR, and PLR; and >3 metastatic sites were found to be independent risk factors in univariate analysis, but NLR was the only independent risk factor in multivariate analysis.ConclusionLow pretreatment and decrease in NLR and DNLR values, and regression/stable disease after 3 months of pazopanib are predictive factors for longer OS and PFS.

Sox9 Enhances Sorafenib Resistance Through Upregulating ABCG2 Expression in Hepatocellular Carcinoma

Sorafenib is a multikinase blocker and the only suggested drug treatment for aggressive hepatocellular carcinoma (HCC) patients. However, drug resistance to sorafenib often occurs after a period of time and cause further tumor aggression. Cancer stem cells are recently found in HCC and regarded to be involved in this process. Sox9 is highly expressed in HCC cancer stem cells and promotes cell proliferation and self-renewal. Meanwhile, HCC patients with higher Sox9 expression show poorer prognosis. Whether Sox9 is involved in sorafenib resistance in HCC is still unclear. Here, we found that sorafenib treatment increased Sox9 expression in HCC cell lines. Overexpression of exogenous Sox9 in HCC increased sorafenib resistance both in vitro and in vivo, and such phenomenon could be inhibited when Sox9 was down-regulated. We checked the down-stream gene expression profile through Sox9 RNA interference and found ATP binding cassette subfamily G member 2 (ABCG2) expression was closely affected by Sox9. Furthermore, we overexpressed Sox9 in combination with ABCG2 inhibition in HCC cell lines, and confirmed that the drug resistance to sorafenib could be ameliorated. In the cohort of patients who took sorafenib, we found those with lower Sox9 expression had longer OS and PFS. Cox analysis shows that Sox9 expression is an independent risk factor of HCC and logistic regression analysis reveals that Sox9 expression, tumor capsule deficiency, tumor diameters and microvascular invasion are risk factors of prognosis of HCC patients. Conclusion: These findings demonstrate that Sox9 enhances sorafenib resistance of HCC and meanwhile Sox9 may regulate such process through modulating ABCG2 expression. Funding: Natural Science Foundation of China. Declaration of Interest: We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work, there is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in, or the review of, the manuscript entitled ”Sox9 enhances sorafenib resistance through upregulating ABCG2 expression in hepatocellular carcinoma”. Ethical Approval: The animal experiments in this study conformed to the Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines and were approved by the Institutional Animal Care and Use Committee of Second Military Medical University (Shanghai,China).

Long-term survival in patients with NSCLC treated with single-fraction vs. multi-fraction palliative radiotherapy in the case of lung tumor, brain metastases and bone metastases

Background: Patients with advanced non-small cell lung cancer (NSCLC) are candidates for different types of treatment, including chemotherapy and radiotherapy or supportive care. Despite the fatal prognosis in advanced disease, many experienced radiation oncologists will apply radiation at low doses with the intention of palliative care. Methods: We used an extensive database of medical patients diagnosed with NSCLC, treated with palliative radiotherapy at the Oncology Centre in Bydgoszcz, from June 1998 to December 2013. A group of 3202 patients was divided into subgroups: Group A)1762 patients irradiated on the lung tumor (without distant metastases): Total dose: A1) 6Gy/1 fr.(n=19); A2) 8Gy/1fr.(n=276); A3) 20Gy/5fr.(n=1349); A4) 30Gy/10fr.(n=118). Group B) 548 patients irradiated on the central nervous system (CNS) metastases: B1) 20Gy/5fr.(n=476); B2) 30Gy/10fr.(n=72). Group C) 892 patients irradiated on the bone metastases: C1) 8Gy/1fr.(n=452); C2) 10Gy/1fr.(n=30); C3) 20Gy/5fr.(n=341); C4) 30Gy/10fr.(n=69). Results: Patients with irradiation of a lung tumor: The longest OS was observed in the group of patients irradiated with doses of 20 Gy (76%) and 30 Gy (7%). Patients with irradiation of bone metastases: No significant differences in OS were observed between the employed fractionation regimens. Patients with irradiation of CNS metastases: The choice of a higher dose of radiation therapy did not demonstrate differences in median OS values compared to a lower dose. Conclusions: The patients who were prescribed single fraction palliative radiotherapy did not have poorer prognoses or experience shorter survival than patients who were prescribed multi-fraction pRT in the case of lung tumor, brain metastases and bone metastases.

Secondary breast angiosarcoma: A multicentre retrospective survey by the national Italian association of Breast Surgeons (ANISC)

BackgroundBreast angiosarcoma is a malignant mesenchymal neoplasm, which accounts for approximately 2% of all soft tissue sarcomas. Secondary breast angiosarcoma (SBA) may be related to chronic lymphedema after a mastectomy with lymph node dissection (Stewart Treves syndrome) and previous radiotherapy for complications from breast radiation treatment. It is a very rare condition; therefore, diagnosis and management are still a challenge. MethodsThe ANISC collected SBA data by means of a survey sent to all Italian breast centres in the ANISC. The clinicopathological characteristics and the management of this disease were analysed. ResultsTwenty-four centres participated in this survey in which 112 cases of SBA were analysed. The median age of the women with SBA was 68.9 years and it appeared approximately 90 months after the first irradiation for breast cancer. In 92% of cases, a mastectomy was performed without axillary dissection for those patients having a high grade of SBA (74.2%). The prognosis was worse in the high-grade cases (overall survival-OS: 36 months) as compared with the low-grade cases (OS: 48 months). After a follow-up of 5 years, 50.5% of the patients were still alive.Disease-free survival (DFS) was 35 months, and there were no differences between the groups of patients with either high- or low-grade histology. ConclusionsSecondary breast angiosarcoma is a very aggressive disease associated with a short survival outcome. The surgical approach still remains an important step in the course of treatment; furthermore, an accurate histological examination is helpful in establishing the prognosis of the patient. A mastectomy is mandatory. A longer OS was observed in patients with low-grade angiosarcoma as compared to high-grade angiosarcoma (C.I. 40–57 vs. 31–41 months).

Characterization of PSA at death in patients with metastatic castration-resistant prostate cancer.

184 Background: Prostate Specific Antigen (PSA) is a valuable prognostic and predictive biomarker in prostate cancer (PC). Currently, the significance of PSA at death is undefined. In this single institution retrospective study, we aim to characterize the significance of PSA at death in patients with metastatic castration-resistant prostate cancer (mCRPC). Methods: Using the Mount Sinai Genitourinary (GU) Cancer Biorepository, an IRB approved database containing all consented GU cancer patients seen between 2010-2018, we stratified patients into the following cohorts based on their PSA at death: &lt; 10, 10-100, 100-1000, and &gt; 1000 ng/ml. We excluded data of patients who had less than 3 visits to the Mount Sinai Hospital. A descriptive analysis was performed to assess clinical characteristics of disease, treatment response, and outcomes. Results: We identified 1097 PC patients, and 101 were found to be deceased following a diagnosis of mCRPC. Cohorts of higher PSA level at death were associated with: a lower Gleason score at diagnosis, a longer time to castration resistance, higher burden of metastatic disease at death (non-visceral and visceral), and longer OS in patients with mCRPC (see table). Conclusions: In this study, PSA at death is associated with several important clinical characteristics and outcome, including overall survival. These differences may be attributed to their underlying biologic behavior. These results are hypothesis generating, and larger studies will be needed to further assess the significance of these findings. [Table: see text]

Phase II trial of VEGFR2 inhibitor apatinib for metastatic sarcoma: focus on efficacy and safety

Apatinib (YN968D1) is a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor 2 (VEGFR-2). We conducted a single-arm, nonrandomized phase II study (NCT03121846) to assess the efficacy and safety of apatinib in patients with stage IV sarcoma. We recruited 64 patients with stage IV sarcoma who had failed chemotherapy. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were progression-free survival rate (PFR), objective response rate (ORR), and disease control rate (DCR) at week 12. Treatment-related adverse effects (AEs) were evaluated. Fifty-nine patients were assessed for efficacy and 64 patients for AEs. The median PFS was 7.93 months. At 12 weeks, the PFR was 74%, the ORR was 16.95% (10/59), and the DCR was 86.44% (51/59). The final ORR was 15.25% (9/59) and the DCR was 57.63% (34/59). Notably, 22 patients (34.38%) who developed hypertension, hand-foot-skin reaction, or proteinuria had significantly longer OS than those without these AEs (18.20 vs. 10.73 months; P = 0.002). We conclude that apatinib is effective and well tolerated in patients with advanced sarcoma. The development of hypertension, hand-foot-skin reaction, or proteinuria may indicate a favorable prognosis, representing a novel finding in sarcoma patients.

Abstract GS3-07: Clinical utility of circulating tumor cell count as a tool to chose between first line hormone therapy and chemotherapy for ER+ HER2- metastatic breast cancer: Results of the phase III STIC CTC trial

Abstract Background: In ER+ HER2- metastatic breast cancer (MBC) patients, the clinical choice between 1st line hormone therapy (HT, the recommended option) or chemotherapy (CT) is based on the absence of “visceral crisis” or adverse prognostic factors, with no proven/objective criteria. In that context, STIC CTC (NCT01710605) was set up as a strategy trial to test whether circulating tumor cells (CTC) count could help customize the choice between 1st line HT or CT. Methods: For this multicenter phase 3 non-inferiority trial, the main inclusion criteria were: ER+ HER2- MBC with no prior therapy, PS≤2, no contra-indication to HT or CT and informed consent. The a priori treatment choice (HT or CT) and CTC count (CellSearch®) were obtained in all patients prior to randomization. Patients were randomized 1:1 between clinically-driven choice (CTC count not disclosed, HT or CT administered as decided a priori), or a CTC-driven choice (HT if &amp;lt;5 CTC/7.5ml, CT if ≥5 CTC/7.5ml). The primary objective was treatment efficacy (PFS hazard ratio), non-inferiority being established if the upper bound of the PFS HR 2-sided 90%CI is ≤1.25; secondary objectives included subgroup analyses (CTC status, patient characteristics) and OS. Results: 761 MBC patients were randomized between 02/2012 and 08/2016. Baseline characteristics: 7.8% of patients had a PS=2, 24.1% had a de novo metastatic disease; 63.3% received prior adjuvant HT and 49.9% prior adjuvant CT; 31.3% had ≥3 metastatic sites. A priori treatments (HT or CT) and CTC count (&amp;lt; or ≥5 CTC/7.5ml) were well balanced between the two arms. After randomization, in the clinically-driven arm, N=267 (72.4%) patients received HT and N=102 (27.6%) CT (as decided a priori). In the CTC-driven arm: (1) the a priori choice of HT was confirmed by a low CTC count in N=181 (67.5%) of patients, while N=87 (32.5%) were switched to CT due to a high CTC count; (2) the a priori choice of CT was confirmed by high CTC count in only N=48 (48%) patients, while N=52 (52%) were switched to HT. The primary endpoint was met, PFS being not inferior in the CTC-driven arm (HR=0.98, 90%CI=[0.84–1.13]). Analyses focusing on discordant subgroups showed that for patients with a priori choice of HT but with high CTC count (leading to a switch to CT in the CTC-arm), PFS was significantly longer in the CTC-driven arm than in the standard arm (HR=0.67, 95%CI=[0.49–0.92]; p=0.01), with a non-significant trend toward longer OS (HR=0.68, 95%CI=[0.44–1.07]; p=0.09). Inversely, for patients with a priori choice of CT but with low CTC count (i.e. de-escalation to HT in the CTC arm), PFS was not statistically different between the two arms. Conclusion: This trial demonstrates the clinical utility of CTC count as an objective decision tool when considering 1st line therapy in ER+ HER2- MBC. In most patients, CTC count did confirm the a priori clinical choice; however, trial results show that in discrepant cases, CTC count may be trusted for either escalating (i.e. considering CT in patients if high CTC count) or de-escalating (i.e. considering HT in patients if low CTC count) 1st line therapy. Funding: French National Cancer Institute; Menarini Silicon Biosystems. Citation Format: Bidard F-C, Jacot W, Dureau S, Brain E, Bachelot T, Bourgeois H, Goncalves A, Ladoire S, Naman H, Dalenc F, Gligorov J, Espie M, Levy C, Ferrero J-M, Loirat D, Cottu P, Dieras V, Simondi C, Berger F, Alix-Panabieres C, Pierga J-Y. Clinical utility of circulating tumor cell count as a tool to chose between first line hormone therapy and chemotherapy for ER+ HER2- metastatic breast cancer: Results of the phase III STIC CTC trial [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr GS3-07.

Abstract P3-01-14: Diverse inter- and intra-patient circulating tumor cells (CTCs) phenotypic heterogeneity identified in metastatic breast cancer (MBC) cohort

Abstract Background: There is unmet need for biomarkers to guide the treatment selection in MBC. We described phenotypic CTC heterogeneity in metastatic castrate resistant prostate cancer(mCRPC), and showed that pts with CTC high heterogeneity have improved OS with chemotherapy, while with pts low CTC heterogeneity pts have longer OS with AR inhibitors (Scher et al. 2017 Cancer Research). Here, the same methodology was applied to evaluate the feasibility of CTC heterogeneity analysis in MBC pts. Material and methods: 92 blood samples from MBC pts were processed for HER2 CTC analysis utilizing the Epic Sciences platform. Following enumeration, multi-dimensional phenotypic characterization analysis was performed utilizing protein expression and digital pathology features. 20 features from each CTC were clustered using unsupervised approach (K-means) and the optimal number of clusters was determined using the elbow method with greater than 85% of variance taken into account. Shannon Index was used to score intra-patient CTC heterogeneity. Results: CTCs were detected in 77.2% (71/92) of the MBC pts. 1501 CTCs from 60 pts were clustered into phenotypic subtypes which are distinctively different in nuclear size, circularity, CK and HER2 intensity etc. HER2 expression was enriched in cell types that had higher CK intensity and was more circular morphologies often associated with replicative stress. A wide range of CTC phenotypic heterogeneity was observed across pts, Shannon Index scores from 0 (low heterogeneity) to 1.67 (high heterogeneity) with a median of 0.60. CTC heterogeneity was independent of CTC counts, some low count pts had heterogeneous CTC subtypes while some high count pts had homogeneous CTC subtypes. Conclusions: Diverse inter- and intra-patient phenotypic CTC heterogeneity were observed in this MBC cohort, consistent with that seen in mCRPC and other MBC cohorts (Beverly H et al, ASCO 2018). Studies linking degree and patterns of CTC heterogeneity to therapeutic outcomes are ongoing. Citation Format: Wang Y, Hom B, Ontiveros P, Landaverde C, Roth E, Levin MK, Hippely S, Landers M, Dittamore R, O'Shaughnessy JA. Diverse inter- and intra-patient circulating tumor cells (CTCs) phenotypic heterogeneity identified in metastatic breast cancer (MBC) cohort [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-01-14.

Minimal Residual Disease (MRD) Assessment before and after Autologous Hematopoietic Cell Transplantation (AutoHCT) and Maintenance for Multiple Myeloma (MM): Results of the Prognostic Immunophenotyping for Myeloma Response (PRIMeR) Study

PRIMeR is the first U.S.-based ancillary study of MRD assessment by multiparameter flow cytometry (MFC). Patients were enrolled on a national 3-arm RCT (BMT CTN 0702, STAMiNA trial, ClinicalTrials.gov Identifier: NCT01109004) comparing 1) tandem auto-HCT, 2) single auto-HCT and 3) single auto-HCT, 4 cycles of lenalidomide, bortezomib, dexamethasone consolidation (auto+RVD); all 3 treatment arms included continuous lenalidomide maintenance until MM progression. STAMiNA opened to accrual before PRIMeR initiated, therefore 437 of 758 patients enrolled in STAMiNA provided consent and at least one analyzable sample for MRD by MFC to PRIMeR. Disease responses and progressions were adjudicated by an independent review committee. All analyses of treatment arm were performed using intent-to-treat. The MFC panel included 10 monoclonal antibodies (CD38, CD138, CD45, CD56, CD19, CD20, CD27, CD28, kappa, lambda) measured via 3 tubes of 6 colors each with a target of analyzing 2.5 × 105-1.5 × 106 events, depending on sample quality and quantity, yielding a sensitivity of 10−5 to 10−6. All samples were interpreted by two experienced flow cytometrists who were blinded to treatment arm and other patient, disease and treatment characteristics. MRD was assessed at Baseline/pre-AutoHCT (BL), Pre-maintenance (PM), and 1 year (Y1) post AutoHCT with the primary endpoint of MRD negative at Y1. At a median follow-up of 38 months, there was no significant difference in PFS or OS by treatment arm in the subset of PRIMeR patients. Univariate analysis demonstrated that being MRD negative at PM and Y1 was associated with better PFS, and at Y1, patients who were MRD negative also had longer OS (Table 1, Figures). Multivariate analysis of time to progression or death, adjusting for disease risk, demonstrated hazard ratios (HR) in MRD negative patients compared to MRD positive patients at BL, PM and Y1 were 0.66 (p=0.07), 0.48 (0

The Prognostic Significance of Pre and Post Treatment Neutrophil to Lymphocyte Ratio in Breast Cancer Patients

Background: The neutrophil/lymphocyte ratio (NLR) has been reported to reflect systemic inflammation and independent prognostic significance in different types of cancer. In present study, we analyzed the association between NLR and clinicopathologic features and verified the significance of NLR as a prognostic factor for patients with breast cancer. Patients and Methods: A total of 388 patients with stage I - III breast cancer were retrospectively recruited into this study. Associations with clinicopathologic factors and NLR were assessed; disease-free survival and overall survival were estimated. Results: There was no significant association between NLR and clinicopathologic factors. Patients with low pre/post-treatment NLR had longer OS. Conclusion: A high pre/postoperative NLR may be considered an important factor for predicting poor prognosis in non-metastatic breast cancer patients.

Effect of Gender on the Outcome of Patients Receiving Immune Checkpoint Inhibitors for Advanced Cancer: A Systematic Review and Meta-Analysis of Phase III Randomized Clinical Trials

Evidence has recently emerged on the influence of gender on the immune system. In this systematic review and meta-analysis of phase III randomized clinical trials (RCTs), we explored the impact of gender on survival in patients with advanced cancer treated with immune checkpoint inhibitors (ICIs). We performed a comprehensive search of the literature updated to April 2018, including the Cochrane Central Register of Controlled Trials, PubMed, and EMBASE. We extracted data on study characteristics and risk of bias in duplicate. Of 423 unique citations, 21 RCTs were included, inherently to 12,635 patients. Both males and females showed reduced risk of death associated with ICIs use (HR 0.73, p < 0.001 and HR 0.77, p < 0.001, respectively). Subgroup analyses by specific ICI showed similar OS in both genders for anti-PD-1/PDL-1. Anti-CTLA-4 use was associated with longer OS in men only (HR 0.77, p < 0.012), with the exception of melanoma (in women, HR 0.80, p = 0.006). PFS was longer in men than in women (HR 0.67, p < 0.001 and HR 0.77, p = 0.100, respectively). Conclusively, ICIs use was associated with more favorable outcomes in men, particularly for anti-CTLA-4 agents. In melanoma, not gender-related factors may influence the anti-tumor immune response evoked by ICIs.