bluuebunny/crossref_metadata_2025 huggingface dataset:
Quantitative measurement of HER3 total protein (H3T) and association with clinical outcome in HER2-positive metastatic breast cancer patients treated with trastuzumab
Authors: Goodman L. J. , Weston J. K. , Mukherjee A. , Sperinde J. , Paquet A. , Williams S. , Parry G. , Bates M. , Koestler W. , Lipton A.
Published: August 2020

1021

Background: The heterodimerization of HER3, with HER2 and the subsequent activation of the AKT pathway, has been implicated in both regulation of tumor cell growth and in resistance to HER2 targeted therapies such as trastuzumab. Currently available methods of measuring H3T in formalin-fixed, paraffin-embedded (FFPE) samples are insufficiently sensitive or specific; thus the impact of quantitative measurement of H3T expression on clinical response to trastuzumab has not been evaluated. Methods: We have developed a highly quantitative, accurate, precise, sensitive, and reproducible H3T assay in FFPE samples based on the VeraTag technology platform. Consequently, the H3T assay displays ∼5-fold greater sensitivity than conventional IHC measurements. Additionally, the rank order and accuracy of the H3T measurements were preserved over a wide dynamic range in well-characterized cell line panels. Intra- and inter-assay reproducibility measurements demonstrated 7–11 %CV and 8–16 % CV, respectively. Results: Quantitative levels of HER2 total protein (H2T) and H3T expression were determined by the VeraTag technology in 81 tumors from patients with trastuzumab-treated metastatic breast cancer. A previously reported H2T cutoff was used to sub-divide the patients into HER2-normal (N = 26, median TTP = 4.1 mos) and HER2-overexpressing (N = 55, median TTP = 11.1 mos, HR = 0.43, p = 0.0002) groups. In the HER2-overexpressing group, high H3T expression, as defined by a positional scanning cutoff analysis, predicted shorter median time to progression (N = 25, median TTP = 6.1 mos) compared with low H3T expression (N = 30, median TTP = 13.1 mos, HR = 2.7, p = 0.0002). Univariate Cox proportional hazards analyses examining the HER2-overexpressing subgroup identified H3T (high vs. low) as the most significant predictor of TTP (HR = 2.98, p = 0.0004). Conclusions: These results demonstrate that the accurate and sensitive measurement of H3T in a cohort of patients with HER-2 positive breast cancer predicts TTP in response to trastuzumab and could indicate a population of patients with worse outcome requiring additional therapeutic intervention.

[Table: see text]
The role of systemic treatment after whole brain radiotherapy (WBRT) in breast cancer patients with brain metastases: Differences depending on biological subtype
Authors: Niwinska A. , Murawska M. , Lemanska I. , Milewska J.
Published: August 2020

1027

Background: The aim of the study was to analyze the efficacy of systemic treatment (chemotherapy [chth], endocrine therapy, targeted therapy) performed after WBRT in patients (pts) with breast cancer and brain metastases. Methods: The group of 222 consecutive breast cancer pts with brain metastases treated in one institution in the years 2003–2006 was divided into four biological subgroups based on ER, PR, and HER-2 receptors’ expression: HER-2(+++)ER/PR(-); HER-2(+++)ER/PR(+); ER(-)PR(-)HER-2(-); and ER/PR(+)HER-2(-). WBRT was performed in 219 (99%) pts. Systemic therapy after WBRT was continued in 160 (72%) pts. Clinically, patients with triple-negative breast cancer were more often in poor performance status (KPS<60%) than the others (51% vs. 28%, respectively). Survivals from brain metastases without and with systemic treatment were compared in four mentioned biological subgroups. Results: Median survival from brain metastases in the entire group was 7.5 months. In the group of ER/PR(+)HER-2(-) median survival without and with systemic therapy was 3 and 14 months, respectively (p = 0.007). In the group of HER-2(+++)ER/PR(+) median survival without further treatment, after chth and after chth with trastuzumab was 2, 8, and 13 months, respectively (p = 0.000) and in the group of HER-2(+++)ER/PR(-) median survival without further treatment, after chth and after chth with trastuzumab was 4, 8, and 10 months, respectively (p = 0.004). In triple-negative breast cancer patients median survival without and with chemotherapy was 3 and 4 months, respectively (p = 0.75). Conclusions: Systemic treatment (chth, endocrine therapy, targeted therapy) continued after WBRT in breast cancer pts with brain metastases prolongs survival in three of four biological subgroups. In the group of HER-2-positive breast cancer pts, trastuzumab added to chth had independent positive impact on survival. No benefit was observed in the subgroup of triple-negative breast cancer pts; it would be the result of refractory disease and the fact, that more pts were in poor performance status.

No significant financial relationships to disclose.
Preliminary results from a phase II study of ARQ 197 in patients with microphthalmia transcription factor family (MiT)-associated tumors
Authors: Goldberg J. , Demetri G. D. , Choy E. , Rosen L. , Pappo A. , Dubois S. , Geller J. , Chai F. , Ferrari D. , Wagner A. J.
Published: August 2020

10502

Background: ARQ 197 is a selective, non-ATP competitive inhibitor of c-Met, a receptor tyrosine kinase implicated in tumor cell migration, invasion, and proliferation. The drug has demonstrated a favorable safety profile and preliminary anti-cancer activity in three phase 1 studies. MiT tumors include clear cell sarcoma (CCS), alveolar soft part sarcoma (ASPS), and translocation-associated renal cell carcinoma (TLA RCC) and are linked biologically by a shared activated transcriptional mechanism which directly upregulates c-Met. Tumors with this type of chromosomal abnormality are generally resistant to all approved therapies and, in the absence of complete surgical resection, prove invariably fatal. Methods: This is a multi-center, single arm, two-stage phase 2 trial in patients (pts) 13 years of age or older with MiT tumors. Initially pts received 120 mg ARQ 197 orally twice daily (bid). The protocol was amended in August 2008 to increase the dose to 360 mg bid. If either a complete response (CR) or a partial response (PR) were to be observed in the 23 pts in stage 1, the study would be advanced to stage 2 where 16 additional patients will be enrolled. Tumor responses are measured in 8-week intervals per RECIST criteria. Results: To date, 28 pts (19 females, 9 males; median age = 21; 7 CCS, 17 ASPS, 4 RCC) have been treated. One pt with CCS demonstrated a confirmed PR, 15 pts (10 ASPS, 2 CCS, 3 RCC) demonstrated stable disease (SD) for durations up to 29+ weeks, and 4 pts progressed. An overall response rate of 5% and a disease control rate (CR+PR+SD) of 80% were demonstrated among 20 pts who were evaluable for efficacy. The most common drug-related adverse events (AEs) have been fatigue (35.7%), nausea (35.7%), vomiting (21.4%), decreased hemoglobin (10.7%). and cough (10.7%). To date, only 3 drug-related Grade 3 or 4 AEs have been reported including anemia (2) and decreased neutrophil count (1). No drug-related serious AEs or deaths have been reported. Conclusions: To date, ARQ 197 has demonstrated an extremely favorable safety profile and preliminary evidence of anti-cancer activity in these young pts. The criterion for advancing the study from stage 1 to stage 2 has been met. Stage 2 enrollment is ongoing. Updated data on both dose levels will be presented.

[Table: see text]
Time to secondary resistance (TSR) after interruption of imatinib: Updated results of the prospective French Sarcoma Group randomized phase III trial on long-term survival
Authors: Duffaud F. , Ray-Coquard I. , Bui B. , Adenis A. , Rios M. , Bertucci F. , Chabaud S. , Perol D. , Blay J. , LeCesne A.
Published: August 2020

10508

Background: We previously demonstrated that imatinib mesylate (IM, Gleevec/Glivec; Novartis Pharma) must not be interrupted after 1 and 3 years (yr) in responding patients (pts) and has to be given continuously until disease progression (PD) or intolerance. The impact of IM re-introduction at progression remains unknown regarding the impact of the interruption on the TSR. Methods: This prospective national multicenter BFR14 study was initiated in June 2002. After 1, 3, and 5 yrs of IM 400mg/day, pts free from progression were randomly offered to continue (C arm) or interrupt (I arm) IM. Pts allocated to the I arm could restart IM (same dose) in case of PD. Primary endpoint was PFS. Pts declining randomization proceed with IM. Results: As of December 2008, 415 pts were included in this trial. Fifty-eight, 50 and 12 (ongoing) non progressive pts at 1, 3 and 5 yrs respectively were randomized in the I and C arm. Pt characteristics were well balanced between the two arms. The median time to progression (TTP) were 7.3 months (m) (rate of relapse: 91% of pts) and 9.4 m (rate of relapse: 84%) in the I arms after 1 and 3 years of treatment. In contrast the median TTP were 31.4 m and not reached in the C arms after 1 and 3 yrs of IM treatment respectively. IM reintroduction in the I arm after a re-progression allowed again a tumor control in 93% (43/46) of pts. The median follow-up from randomization is 56 m and 25 m at 1 and 3 yrs respectively. TSR after randomization to IM (first progression in the C arm, 2nd progression in the I arm) was not significantly different between the two arms (the 2-yrs TSR is similar in both arms 63% and 62% in the I and C arm respectively for the 1-yr randomization, 83.5% and 84.3% for the 3-yr randomization) but the rate of secondary resistance decrease over time in both arms: 40% or relapse in the 2 yrs following the 1 yr randomization vs less than 20% or relapse in the 2 yrs following the 3-yrs randomization. Conclusions: The majority of responding pts relapsed when IM was stopped after 1 and 3 yrs of treatment but response is reinduced in 93% of patients after IM reintroduction. TSR was not significantly affected by treatment interruption in this series of pts.

[Table: see text]
Chordoma of the mobile spine: A retrospective analysis on 146 patients from two reference centers
Authors: Stacchiotti S. , Lo Vullo S. , Mercuri M. , Mariani L. , Alberghini M. , Pilotti S. , Ferrari S. , Casali P. G. , Gronchi A. , Picci P.
Published: August 2020

10517

Background: The natural history of chordoma is still poorly known. Methods: We reviewed a large series of patients (pts) from two major reference centers for chordoma. All pts presenting at Istituto Ortopedico Rizzoli, Bologna, and Istituto Nazionale Tumori, Milan, Italy, over 25 years, were reviewed. Clinical and pathologic characteristics were recorded. Local recurrence, distant metastasis, and overall survival (OS) were analyzed both from time of diagnosis and from time of local recurrence/distant metastasis. A multivariable analysis to identify independent prognostic factors was carried out. PDGFR and brachyury expression analysis is ongoing. Results: One hundred forty-six consecutive pts were identified (sacrum 79%, lumbar spine 15%, cervical-dorsal spine 6%; extension at diagnosis: localized 90%, locally-advanced 5%, metastatic 5%; median size 10 cm, IQ range: 6–14). Median follow-up was 140 months (IQ range: 80–205). The 5/10-year OS, local relapse-free survival (LRFS) and distant relapse-free survival (DRFS) were respectively: 76/52%, 51/32%, 86/72%. For pts with primary disease, size independently predicted OS (p-value: 0.004), LRFS (p-value: 0.006) and DRFS (p-value: 0.02), while surgical margins independently predicted only LRFS (p-value: 0.0001) with a trend for OS (p-value 0.1007). Radiotherapy performed in 44 pts did not influence LRFS nor OS, but only 9 pts received >60 Gy. The 5/10-year OS, LRFS, DRFS after the first local relapse were 54/24%, 50/45%, 64/61%. Size of the recurrence and quality of surgical margins did not influence post-relapse OS. The 5/10-year OS after the second local relapse were 20/0%. The overall incidence of metastases was 32% (commonest site: lung). The 5/10-year post-metastases OS was 35/0% (median 3 years). Results on PDGFR and brachyury expression will be provided. Conclusions: Tumor size and surgical margins affected outcome only on initial presentation. Incidence of distant metastases was higher than expected, although with a more indolent course than generally supposed. In spite of its indolent behavior, long-term prognosis was poor, with 26% of pts being continuously disease-free at 10 years. This series may provide an external control for studies on novel targeted agents, which are proving effective in such a rare tumor.

No significant financial relationships to disclose.
Correlation of gastrointestinal stromal tumor (GIST) gene expression signatures and response to imatinib mesylate in the Radiation Therapy Oncology Group phase II clinical trial S-0132
Authors: Rink L. , Skorobogatko Y. , Kossenkov A. , Belinsky M. G. , Pajak T. F. , von Mehren M. , Ochs M. F. , Eisenberg B. , Godwin A. K.
Published: August 2020

10533

Background: Despite the known efficacy of imatinib mesylate (IM) in metastatic GIST, both primary and secondary drug resistance remain a clinical problem. Therefore, future management of GIST may benefit from further molecular characterization associated with IM treatment. Methods: A recently completed prospective phase II trial of neoadjuvant/adjuvant IM treatment for advanced primary and recurrent operable GISTs included gene expression profiling using oligonucleotide microarrays on tumor samples obtained before and after neoadjuvant IM therapy for 8 to 12 weeks. Fifty-two analyzable patients were classified according to changes in tumor size after IM based on CT scan measurements. A response was defined as >25% tumor reduction. Gene profiling data were then evaluated with SAM analysis (FDR = 10%) to identify differentially expressed genes (in pre-treatment GIST samples). In addition, a custom siRNA library was designed targeting these genes and a mid-throughput siRNA synthetic lethal screening approach was used to evaluate the ability of each to sensitize GIST cells to IM. Results: Thirty-eight genes were expressed at significantly lower levels in the pre-treatment samples of tumors that rapidly responded to IM. Eighteen of these genes encoded KRAB domain containing zinc finger (KRAB-ZNF) transcriptional repressors. Importantly, ten KRAB-ZNF genes mapped to a single locus on chromosome 19p, and a subset of these predicted likely response to IM-based therapy in a naïve panel of GISTs. Further evaluation revealed that modifying in vitroexpression of genes via RNAi approaches within this predictive response signature enhanced the sensitivity of GIST cells to IM. Conclusions: Using clinical samples from a prospective neoadjuvant/adjuvant phase II trial we have identified a genetic signature which includes KRAB-ZNF 91 subfamily members that may be both predictive of and functionally associated with likely rapid response to short-term IM treatment and which may provide a prognostic biomarker identifying patients who will benefit from it.

[Table: see text]
Assessment of the heat shock protein 90 (HSP90) inhibitor IPI504 alone or in combination with the tyrosine kinase inhibitor (TKI) imatinib in mice carrying xenografts of human gastrointestinal stromal tumors (GIST)
Authors: Schoffski P. , Floris G. , Sciot R. , Stefan C. , Wozniak A. , Machiels K. , Normant E. , Debiec-Rychter M.
Published: August 2020

10534

Background: Inhibition of HSP90 is a new strategy for treatment of GIST. IPI-504 is a potent i.v. HSP90 inhibitor. We assessed the activity of IPI-504 in imatinib-sensitive GIST xenografts, alone/combined with the TKI. Methods: Human GIST882 cells (KIT exon 13 mut.) were grafted in 43 nude mice, who were randomized to 4 groups: A (n=13; control); B (n=18; IPI-504 100 mg/kg 3x/wk p.o.); C (n=8; imatinib 50 mg/kg 2x/d p.o.); D (n=4; IPI-504+imatinib, dose/schedule as above) for 2 weeks. Histopathological assessment was done by H&E and KIT immunostaining, histological response (HR) was defined by magnitude of necrosis and myxoid degeneration [grade 1 (0–10%), 2 (>10% - ≤ 50%), 3 (> 50% - ≤90%), 4 (>90%)]. Expression/activation of KIT and its signaling (AKT, S6, MAPK) was assessed by Western blot. Results: IPI-504 alone significantly reduced tumor volume (41%) at day 14, further enhanced by adding imatinib (58%). Imatinib alone led to only a 5% reduction. IPI-504 induced grade 2 HR in 17/36 tumors, while the majority of tumors (13/15) treated with imatinib showed grade 1 HR. Grade 3/4 HRs were only seen with the combination. Mitosis decreased 3.3-fold, apoptosis increased 1.3-fold with IPI-504. Despite substantial reduction in mitotic activity in C and D (8.2- and 82-fold), apoptosis was virtually unaffected. In the IPI-504 arm, KIT levels were partially downregulated. Imatinib alone had no effect on KIT expression, while the combination produced a marked suppression of total KIT, accompanied by complete downregulation of the signaling. Loss of KIT in the combination arm was confirmed by immunostaining. Although KIT was not completely degraded with IPI-504, measurable effects on activation of AKT, S6 and MAPK were observed. Conclusions: IPI-504 has consistent antitumor effects in GIST xenografts, both histologically and on the molecular level. Combining IPI-504 with imatinib substantially enhances anti-tumor activity, providing a strong rationale for clinical trials of IPI-504 in GIST as single agent and in combination.

[Table: see text]
Treosulfan-based high-dose chemotherapy with autologous stem cell transplantation in high-risk Ewing sarcoma
Authors: Juergens H. , Ranft A. , Paulussen M. , Kontny U. , Dilloo D. , Dirksen U.
Published: August 2020

10546

Background: High-dose chemotherapy (HDC) is widely used in consolidation treatment of Ewing sarcoma patients with primary disseminated or recurrent disease. Standard busulfan-based regimens are not compatible with radiotherapy to central axis sites. Treosulfan is a newly-developed bifunctional alkylating agent that has been shown to be safe in current trials of the German Society for Pediatric Hematology and Oncology (GPOH) even in heavily pre-treated patients including axial radiation. Methods: Event-free survival (EFS) and overall survival (OS) for 21 patients with primary disseminated disease (PDD) and survival after relapse for 11 relapse patients recruited from the EURO-E.W.I.N.G.99 trial 1998–2007 were analyzed. PDD-patients had received VIDE induction prior to treosulfan-based HDC (treosulfan: 36g/m2; melphalan: 140mg/m2) followed by autologous stem cell transplantation. Median follow up was 1.72 yrs. Relapse patients had received appropriate second line chemotherapy regimens prior to treosulfan-based HDC. Median follow up after relapse was 2.26 yrs. Results: Seventeen of 21 (81%) PDD-patients had a central axis site of the primary tumor, 8 patients (38%) presented with a pelvic tumor. Metastatic sites were: bone (76%), bone marrow (22%), CNS (10%), liver (15%), lymphnode (29%), other (16%), and additionally lung metastases in 57%. 1y-EFS was 0.70 (SE=.10), 2y-EFS was 0.27 (SE=0.10), and 3y-EFS was 0.16 (SE=.09). 1y-OS was 0.84 (SE=.08), 2y-OS was 0.46 (SE=.13), and 3y-OS was 0.32 (SE=.12). In the cohort of 11 relapse patients two patients (18%) had a local relapse, 3 (27%) a combined relapse, and 6 (55%) a systemic relapse. Six of 11 (55%) relapse patients had a late relapse >2 yrs from diagnosis. Survival after relapse at 3yrs was 0.70 (SE=.15). Conclusions: Treosulfan-based HDC is an alternative approach in high-risk Ewing tumor patients especially after relapse to consolidate a second remission. Further investigation and comparison to other standard HDC regimens is needed.

No significant financial relationships to disclose.
Microscopic margins of resection in gastrointestinal stromal tumor (GIST): An analysis of 122 patients
Authors: Di Battista M. , Saponara M. , Pantaleo M. A. , Catena F. , Santini D. , Lolli C. , Di Scioscio V. , Astorino M. , Maleddu A. , Nannini M. , Biasco G.
Published: August 2020

10554

Background: The main treatment for localized GIST is complete surgical resection. The prognosis is strongly correlated with both tumor size and mitotic index. The aim of our study was to analyze retrospectively the outcome of patients affected by GIST related to microscopic margins of resection. Methods: The outcome of 122 patients surgically managed during the past 11 years, were evaluated. We analyzed the impact of R0 and R1 resection on DFS. Results: All patients but one, had a c-Kit positive GIST, 91% had primary disease without metastasis, 9% had metastasis. There were 46% high, 31% intermediate and 28% low risk GIST. The median age was 65 years (range 29–87). The most common sites of tumor origin were the stomach (54.9%) and the small bowel (36.9%). Sites of tumor metastasis were liver (18.2%), peritoneum (36.4%) or both (19.3%). R0 resection was achieved in 102 (83.6%) patients, while 16 pts (13.1%) had positive microscopic margins (R1). With a median follow up of 24 months (range 3–119), recurrence occurred in 34 (33.3%) R0 and in 9 (56.3%) R1 patients. The median DFS was 53.7 months and 35.6 months for the R0 and R1 group, respectively. The difference tested with univariate analysis using Long rank test, was not statistically significant (p= 0.228). Conclusions: In our series, the status of microscopic margins does not appear to be important for prediction of recurrence in patients affected by GIST.

No significant financial relationships to disclose.
Sorafenib fourth-line treatment in imatinib-, sunitinib-, and nilotinib-resistant metastatic GIST: A retrospective analysis
Authors: Reichardt P. , Montemurro M. , Gelderblom H. , Blay J. , Rutkowski P. , Bui B. , Hartmann J. T. , Pink D. , Leyvraz S. , Schütte J.
Published: August 2020

10564

Background: Gastrointestinal stromal tumors (GISTs) are rare mesenchymal tumors usually caused by mutations in the KIT or PDGFRA gene. Advanced disease generally cannot be cured by surgery nor by tyrosine kinase inhibitors (TKI), but TKIs have considerably improved outcome for patients (pts) with advanced GIST. Patients failing TKI treatment with imatinib (IM), sunitinib (SU) or nilotinib (NI) have a poor prognosis. Sorafenib is a multi kinase inhibitor that blocks not only receptor tyrosine kinases such as KIT, VEGFR and PDGFR but also serine/threonine kinases along the RAS/RAF/MEK/ERK pathway. Recently, clinical activity of sorafenib in third-line treatment in patients with GIST after IM and SU failure has been shown (Wiebe et al. ASCO 2008, #10502). Methods: We report herein preliminary data of 32 pts treated with sorafenib in nine European centers. Centers were selected based on their previous and known experience in GIST and reported all pts treated. Pts received sorafenib after failure of IM, SU and NI in fourth-line treatment. Baseline characteristics and treatment details have been retrieved via questionary. Results: Median age at sorafenib treatment start was 62 years (range 33–81 y), and the majority of pts were male (63 %). Primary tumor site was gastric or small intestine in 25% and 41% of pts, respectively. All pts had failed IM, SU, NI. 19 % of pts achieved partial remission and 44% disease stabilization. Approximately half of the pts had an improvement of symptoms and/or performance. Half of the pts were on treatment longer than 4 months (actuarial data) and 41% of pts continue to receive sorafenib. Median progression-free survival is 20 weeks and median overall survival 42 weeks (Kaplan-Meier), at a median follow-up of 22 weeks (range 3–54). Conclusions: This is the largest series assessing efficacy of sorafenib fourth-line treatment for IM, SU and NI refractory GIST reported yet. Sorafenib displays significant clinical activity in this heavily pretreated group of patients.

[Table: see text]
Gastrointestinal stromal tumor associated with other primaries: A study of 154 patients
Authors: Pandurengan R. K. , Strom S. S. , Trent J.
Published: August 2020

10567

Background: The objective of this study is to investigate the characteristics and survival rate of patients with Gastrointestinal Stromal Tumor (GIST) associated with other primary malignancies. Methods: 783 patients with GIST were treated at M. D. Anderson Cancer Center from 1995 to 2007. Multiple primaries included tumors that were not considered to be a metastasis, invasion or recurrence of GIST excluding non-melanoma skin cancer. Data on gender, age at diagnosis of cancer, follow-up time after diagnosis, and death rate were collected. Results: Of the 783 patients, 154 (20%) were identified with at least one other primary other than GIST (GIST+). The ratio of men and women was 1.5 and 1.3 in patients with GIST+ compared to those with GIST only, respectively. Median age at diagnosis of GIST was 57 for patients with GIST only whereas it was 68 in patients with GIST+. The stomach was the frequent site of occurrence in GIST only and GIST+. The total numbers of other primaries developed before the diagnosis of GIST was higher (134) than the primaries developed after the diagnosis of GIST (53). The most frequent primaries observed before the diagnosis of GIST were prostate (25), breast (12), esophagus (9), kidney (7) and melanoma (6). Lung (5) and kidney (5) were the most frequent type of primaries that developed after the diagnosis of GIST. The 5-yr survival was 68% for patients with GIST+ when the other primary occurred before GIST, 61% for patients with GIST+ when the other primary occurred after the diagnosis of GIST, 58% for patients with GIST only, and 49% for GIST++ patients with two or more other primaries (p=0.002). Conclusions: Superior survival in GIST+ patients may be due to the bias of early detection. The etiology and clinical implications of the association of other primaries in GIST patients should be further investigated.

No significant financial relationships to disclose.
CXCR4-CXCL12 axis: Pivotal role as a metastatic mediator in small cell sarcoma
Authors: Dumont S. N. , Aslam M. I. , McAuliffe J. C. , Yang D. , Nolden L. K. , Oyedeji C. O. , Trent J. C.
Published: August 2020

10569

Background: The chemokine CXCL12, and its receptor CXCR4, are expressed in over 23 different types of cancers, and have been associated with the metastatic phenotype and inferior clinical outcomes. Given the poor prognosis after failure of front-line therapy for patients with metastatic Ewing's sarcoma (EWS) and rhabdomyosarcoma (RMS), we examined the functional role of CXCR4 in these small cell sarcoma in vitro. Methods: Human EWS and RMS cell lines and tissue were used to study CXCR4 expression and activation. Immunoblotting techniques were used to evaluate CXCR4 activation and inhibition. Cell viability, cell cycle, apoptosis, chemosensitivity, migration, and invasion assays were utilized to assess the effects of the small peptide CXCR4 antagonist, CTCE-9908 (Chemokine Therapeutics) on cultured cells. Results: CXCR4 was highly expressed on 46 % of human RMS tumor samples. CXCR4 underwent phosphorylation after stimulation with CXCL12 in EWS and RMS cell lines with downstream activation of Akt, p42/44 MAPK, JAK2 and PLCγ1 in select cell lines. CTCE-9908 was able to specifically inhibit downstream signaling of Akt, p42/44 MAPK and JAK2. Decrease in cell proliferation (20–30%, p < .05), increase in cell apoptosis (20–40 %, p < .05) and cell cycle arrest was also observed with CXCR4 blockade. CTCE-9908 significantly inhibited migration and invasion (68–93 %, p < .05) in our cell lines. Conclusions: CXCR4-CXCL12 axis may be important in EWS and RMS metastasis. These results provide evidence that CTCE-9908 may be a novel therapy for these sarcomas.

No significant financial relationships to disclose.
Prognostic factors in adolescents and young adults (AYA) with high-risk soft tissue sarcoma (STS) treated by adjuvant chemotherapy: A study based on two pooled European Organisation for Research and Treatment of Cancer (EORTC) clinical trials
Authors: Kasper B. , Ouali M. , Van Glabbeke M. , Blay J. , Bramwell V. H. , Woll P. J. , Schöffski P.
Published: August 2020

10573

Background: We conducted a retrospective study pooling data from two clinical trials in high risk STS patients with the objective to compare two different age groups: 15 - 29 years (AYA population) and ≥ 30 years. The aim was to determine prognostic factors for the AYA population. Methods: Patients selected for analysis were treated in two randomized trials of adjuvant chemotherapy in STS (EORTC 62771 and 62931). A total of 793 patients were included with a median follow-up (FU) of 8.74 years (AYA population: n = 161, median FU 9.46 years; patients ≥ 30 years: n = 632, median FU 8.62 years). Study endpoints were overall survival (OS) and relapse-free survival (RFS). The variables of the multivariate analysis were gender, subtype and grade, tumor size and localization (limb vs. other), absence or presence of local recurrence and treatment (control arm vs. adjuvant chemotherapy). Results: Patients’ characteristics were globally similar with two exceptions, histological subtype (p = 0.0043) and tumor size (p < .0001). The commonest sarcoma subtype in the AYA population was synovial sarcoma (29 %), whereas leiomyosarcoma (18 %), malignant fibrous histiocytoma (MFH, 16 %) and liposarcoma (15 %) were more frequent in patients ≥ 30 years. For OS, independent favorable prognostic factors were low grade and small tumor size for both groups; radical resection and MFH or liposarcoma subtype were factors of favorable prognosis for patients ≥ 30 years only. For RFS, favorable prognostic factors were small tumor size and low grade for both groups; tumor location in the extremities was a factor of favorable prognosis for the AYA population only, whereas radical resection and adjuvant chemotherapy treatment were favorable factors for patients ≥ 30 years only. Conclusions: On the basis of these data, significant differences could be found concerning prognostic factors between the AYA population and older patients. Interestingly, adjuvant chemotherapy was associated with improved RFS only in patients ≥ 30 years. The results may have further implications on the treatment of STS patients in different age groups as well as the design of future clinical trials.

No significant financial relationships to disclose.
A phase I study of palifosfamide in combination with doxorubicin: Safety and preliminary efficacy
Authors: Camacho L. H. , Chawla S. P. , Chua V. , Abbadessa G. , Komarnitsky P. B. , Lewis J.
Published: August 2020

10577

Background: Palifosfamide, a bi-functional DNA alkylator is the active metabolite of ifosfamide (IFOS), that lacks the toxicity associated with non-active IFOS metabolites and does not require activation. Recent phase II data shows single agent activity in advanced refractory sarcoma. Marked preclinical synergistic efficacy of palifosfamide in combination with doxorubicin provides a strong rationale for clinical evaluation of this combination regimen. Methods: Eligible subjects with advanced refractory tumors were included if no standard therapy exists and if doxorubicin treatment is medically acceptable. Palifosfamide was administered on days 1 - 3 of a 21 day cycle, starting dose of 100 mg/m2. Doxorubicin was administered on day 1 of 21 day cycle, starting dose of 60 mg/m2. Dose was escalated up to MTD or palifosfamide 150 mg/mg2, doxorubicin 75 mg/m2. Pharmacokinetics (PK) for palifosfamide were determined and compared to those obtained in murine PK/efficacy studies. Results: 13 patients with advanced tumors (8 with soft tissue sarcoma - STS, 5 with SCLC, neuroendocrine and osteosarcoma) have been treated with 8 patients still on treatment. All had ECOG PS <2, median age was 58, and 3 had received prior IFOS. With 51 cycles administered, the combination has been well tolerated, with no dose-limiting toxicities reported. Pts did not receive Mesna or hydration. Study-related Grade 3/4 adverse events include neutropenia and thrombocytopenia. PK evaluation indicates that palifosfamide exposure and Cmax at clinically well-tolerated doses are comparable with those in murine models resulting in marked synergy with doxorubicin. Efficacy in 12 evaluable pts: 3/12 PRs, (2/8 PRs for STS); PFS median duration 20 weeks and ongoing. Conclusions: Palifosfamide in combination with doxorubicin is easy to administer, and has been very well tolerated with no encephalopathy, no hemorrhagic cystitis and no renal toxicity. Early efficacy data has prompted an ongoing randomized phase II study in STS comparing doxorubicin 75 mg/m2 to palifosfamide 150 mg/m2 + doxorubicin 75 mg/m2.

[Table: see text]
Circulating tumor cells and risk of venous thromboembolism in metastatic breast cancer patients
Authors: Mego M. , De Giorgi U. , Hsu L. , Andreopoulou E. , Valero V. , Dawood S. , Handy B. , Reuben J. M. , Cristofanilli M.
Published: August 2020

1060

Background: Cancer is well-recognized risk factor for venous thromboembolism (VTE), and VTE is associated with a higher risk of death in cancer patients. Coagulation activation by tissue factor (TF) is associated with cancer growth and disease progression. Circulating tumor cells (CTCs) are an independent predictor of survival in metastatic breast cancer (MBC) patients. The aim of this study was to test the hypothesis that CTCs are associated with the risk of VTE in MBC patients. Methods: This retrospective study included 362 MBC patients treated in M. D. Anderson Cancer Center between January 2004 and December 2007. CTCs were detected and enumerated using the CellSearch system. Patients were assigned to cohorts based on the highest CTC counts during the course of the disease. All venous thrombosis and/or pulmonary embolism in the presence of unequivocal medical documentation were classified as events. Results: At a median follow up of 11.1 months (range 0–38 months) 30 patients (8.3%) experienced VTE. Median survival was 16.3 months vs. 37.2 months (p = 0.003) in patients with and without VTE, respectively. Patients with ≥ 3 CTCs had an elevated risk of VTE in comparison to patients with < 3 CTCs (12.1% vs 3.7%; p = 0.003). In multivariate analysis, the presence of visceral metastasis, increased number of metastatic sites and ≥ 3 CTCs were associated with the risk of VTE. Conclusions: This retrospective study showed that CTCs are associated with increased risk of VTE in MBC. Prospective assessment of coagulation status and its correlation to CTC counts and clinical outcome are warranted.

No significant financial relationships to disclose.
cMET expression in HER2+ MBC patients with first-line lapatinib (L) treatment
Authors: Liu Y. , Liu L. , Shi H. , Greger J. G. , Jackson K. D. , Marty-Ethgen P. , Gilmer T. M. , Martin A.
Published: August 2020

1073

Background: Overexpression of MET correlates with poor prognosis in breast cancer (Garcia et al., 2007) and is a factor associated with decreased sensitivity to L in HER2+ breast tumor cell lines in vitro (Liu et al., submitted). To test whether MET expression was associated with resistance to L in the clinic we evaluated baseline tumor MET expression levels and clinical outcome to L in 64 patients who participated in the EGF20009 trial of monotherapy L as first-line treatment in HER2+ advanced or MBC. Methods: RNA was extracted from FFPE tumors and MET and HER-2 gene expression was measured by qRT-PCR (Response Genetics, Inc., Los Angeles, CA). The correlation between expression levels of MET, HER2, and clinical outcome (overall response and progression free survival) was performed using JMP software. Results: A trend towards an association with increased MET expression and decreased response (p < 0.054) was observed.. Patients with high HER2 and low MET gene expression had the longest PFS (median difference = ∼9 weeks) compared to patients with low HER2 and high MET gene expression (p < 0.0038). Conclusions: These data support investigating a combination study of L and GSK1363089, a multi-kinase MET inhibitor, in HER2+ BC patients with high MET gene expression.

[Table: see text]
New biweekly combination of trastuzumab, docetaxel, and gemcitabine for HER2-positive metastatic breast cancer: First early results from a phase II multicentric trial on behalf of Gruppo Oncologico Italia Meridionale
Authors: Cinieri S. , Orlando L. , Lorusso V. , Filippelli G. , Maiello E. , Blasi L. , Verderame F. , Barni S. , Pisconti S. , Colucci G.
Published: August 2020

1096

Background: The clinical activity of the combination of chemotherapy plus trastuzumab in HER-2 overexpressing metastatic breast cancer has been well documentated. We report the first results in terms of efficacy and safety of a phase II trial on biweekly combination of trastuzumab plus docetaxel and gemcitabine as first line therapy in HER-2-positive metastatic breast cancer patients. Methods: Patients at first relapse or with synchronous metastasis, were treated with trastuzumab (4 mg/kg, loading dose 6 mg/kg) plus gemcitabine (1000 mg/m2) plus docetaxel (50 mg/m2) as biweekly schedule. Primary end-point was overall response rate (ORR), secondary end-point time to progression (TTP), clinical benefit rate (CBR; PR+ CR + prolonged SD for ≥ 24 weeks), and tolerability. Based on previous data, an ORR greater than 60% was considered to indicate clinical activity in this two stage design trial. Results: A total of 26 patients with histologically confirmed, measurable MBC, tumors scored as +3 positive for HER-2 by immuno-histochemistry or FISH +, no pretreated with chemotherapy or trastuzumab for metastatic disease have been enrolled, 22 actually evaluable for response and toxicity. Median age was 49 years (range 34–66), visceral metastases were present in most patients (73%). Median number of cycles was 8 (range 3–12). The ORR was 86% (95% CI, 80–91%), with two CR (9 %) and 17 PR (77%). 3 patients had SD, 1 prolonged (14%). The CBR was 91% (95% CI, 87%-94%). No progression of disease was observed. Median TTP was 7 months (range 5- 9+ months). The worst toxicity was WHO grade 2 neutropenia and grade 2 gastric pain. Conclusions: In this phase II study, the biweekly combination of trastuzumab, gemcitabine, and docetaxel in HER-2-positive breast cancer is very active. The toxicity observed was manageable and did not lead to treatment discontinuation. Thus, the patients accrual is ongoing to the preset target of 50 patients.

No significant financial relationships to disclose.
Cisplatin chemotherapy in the treatment of BRCA1-positive metastatic breast cancer (MBC)
Authors: Byrski T. , Foszczynska-Kloda M. , Huzarski T. , Dent R. , Gronwald J. , Cybulski C. , Debniak T. , Gorski B. , Lubinski J. , Narod S.
Published: August 2020

1099

Background: Preclinical data suggest that women with BRCA1 related breast cancers may be particularly sensitive to chemotherapeutic agents that cause DNA damage such as cisplatin chemotherapy. This study was conducted to assess the efficacy and safety of cisplatin chemotherapy in patients with BRCA1 positive MBC. Methods: This was a multicenter, open label, single arm study of cisplatin 75 mg/m2 given intravenously every three weeks until disease progression or toxicity. The primary objective was to assess antitumour activity of cisplatin, as measured by clinical benefit response (CR, PR, or SD ≥ 6 months). Eligible patients had locally recurrent or MBC, had 0–2 prior chemotherapy regimens in the metastatic setting, and had received prior therapy with an anthracycline. Patients were restaged every eight weeks. The study protocol was approved by the institutional review boards of participating institutions. Results: A total of 15 patients were enrolled. Mean age was 48.1 years (range: 32 to 70). ECOG performance status scores were 0 (6 pts), 1 (5 pts), 2 (4 pts). All patients had a confirmed BRCA1 mutation (7 with C61G mutation, 7 with 5382 insC, 1 with 4153delA). Five patients (33%) were ER or PR + and none were HER-2+. Prior history of MBC chemotherapy included 1 regimen (4 pts) and 2 regimens (7 pts). Seven (46%) and 4 (26%) patients had complete and partial responses by Response Evaluation Criteria in Solid Tumors (RECIST) criteria, for an overall response rate of 72%. Median duration of response has not yet been reached. In general, cisplatin was well tolerated. Neutropenia was the commonest toxicity with 33% grade 2 (6,7% and 0%, grades 3 and 4 neutropenia). No patients developed febrile neutropenia. Conclusions: Significant activity and favorable toxicity profile provides a basis for considering cisplatin for further evaluation in phase III trials for women with BRCA1 positive MBC.

No significant financial relationships to disclose.
Selecting subjects for a therapeutic target in colorectal cancer (CRC): Using a clinical database to enrich for patients harboring the BRAFV600E mutation
Authors: Tie J. , Sieber O. M. , Gibbs P. , Lipton L. , Jorissen R. N. , Langland R. , Kosmider S. , McKay D. , Nolop K. B. , Desai J.
Published: August 2020

11003

Introduction: The BRAFV600E mutation (BRAF) causes constitutive activation of the RAS-induced MAPK pathway and is found in 10% of colon cancers. B-RAF inhibitors are in early clinical development, but their development in CRC will be challenging unless subsets of patients (pts) with higher rates of BRAF can be defined. The mutation rate in rectal tumors, the concordance between primary and metastases, and the prognostic/predictive significance of BRAF are current gaps in knowledge. Methods: 481 primary tumors and 80 matched primary-metastasis (prim-met) pairs were analysed from a pre-defined cohort of pts with CRC based on age (≥ 70 vs < 70 years), gender, tumor site (right-R, left-L and rectum), stage (A to C vs D) and ≥ 2 years follow-up. BRAF was assessed by routine sequencing of exon 15 and by a mutant-specific PCR assay. KRAS (KRAS-codon 12 and 13) and MSI (Bethesda markers) status were also examined. Results: Overall prevalence of BRAF was 11%. BRAF (see table ) was independently associated with increasing age, female gender and R-sided cancer, but not with stage. Mutations were rare in rectal cancers. BRAF was associated with inferior overall survival in stage D pts (log-rank, p = 0.0003; HR 0.38, 95% CI, 0.10–0.51). Survival analysis will be further stratified by treatment received. No difference in outcome was seen in preliminary analysis of earlier stage cancers. Mutation frequencies in the prim-met pairs were 38% (30/80) and 1.3% (1/80) for KRAS and BRAF, respectively. Overall concordance was 88% (70/80) for KRAS and 100% (80/80) for BRAF status. Conclusions: The development of selective B-Raf inhibitors in CRC is potentially more attractive due to the ability to define patient subsets with a higher prevalence of BRAF mutations. Analysis of the primary tumor reliably predicts the status of metastatic disease in the same patient. The association between BRAFand poor outcome will need to be considered when interpreting the result of studies targeting this mutation. [Table: see text]

[Table: see text]
Establishment of human primary non-small cell lung cancer xenograft models for test of cytotoxic and targeted anticancer drugs
Authors: Liu C. , Liu Y. , Chen D. , Tang Z. , Pan W. , Wery J. , Chen Y.
Published: August 2020

11008

Background: New oncology drug development has moved from general cytotoxic agents to molecular target-directed therapeutics. Consequently, there is a need to identify tumor types and individual patient tumors that express the target and could benefit from more selective therapies in clinical trials. Therefore, the in vivo models used in preclinical development should be“disease-oriented” and target-directed. Recently, we developed non-small cell lung cancer (NSCLC) xenograft models by transplanting human fresh tumor fragments into nude mice, which have been used for test of cytotoxic and targeted anticancer drugs. Methods: The fresh NSCLC tumors were collected from local hospitals. The tumor fragments were subcutaneously implanted into nude mice. The EGFR and K-ras mutation status of the tumors were investigated and compared with the efficacy results. The test drugs included paclitaxel, gemcitabine, and the epidermal growth factor receptor (EGFR) inhibitor erlotinib. Results: A total of 72 NSCLC samples were implanted, and 13 tumor models were established (tumor taking rate 18%) for the first passage. The tumor taking rates were higher in the second and third passages (80–100%). Paclitaxel and gemcitatbine produced tumor growth inhibition rates of 50–53% regardless of the EGFR and K-ras mutation status. While erlotinib demonstrated a significant antitumor activity only in the tumors bearing EGFR mutation with wild-type K-ras, which were consistent with their clinical findings. The tumor xenografts’ architecture, the cell and histopathological morphology from the three generations mirrored the original patient cancers. Conclusions: These results suggest that human primary tumor xenograft models provide a unique renewable source of tumor material for test of novel anticancer agents. They may predict more relevant clinical response rates and higher correlation with clinical findings than use of xenograft models established from long-term cultured cancer cell lines, especially for test of target-oriented therapeutics in new drugs development programs.

No significant financial relationships to disclose.
Notch-associated expression profiles in basal-like and claudin-low breast cancer molecular subtypes
Authors: Prat A. , Karginova O. , Fan C. , Perou C. M.
Published: August 2020

11017

Background: An attractive candidate target for breast cancer (BC) and BC tumor-initiating cells is the Notch signaling pathway. To better understand the potential dependence of breast cancer upon Notch-signaling, we used a genomic approach to study the activation of this pathway in the different molecular subtypes. Methods: Breast basal-like, luminal and HER2+ cell lines were examined for sensitivity to gamma-secretase inhibition (GSI). Gene expression data from the most sensitive cell line was analyzed during treatment and upon releasing from GSI (4h, 8h and 24h post-treatment). Using an unsupervised analysis, all time points were hierarchically clustered and genes that changed in expression were identified (SAM one-class). This Notch-associated signature identified in vitro was used to classify 2 distinct sporadic breast tumor populations (UNC and NKI, n=495). Each tumor sample was categorized into 6 molecular subtypes (basal-like, claudin-low [submitted], luminal A/B, HER2-enriched and normal-like). Results: In vitro, breast basal-like cell lines SUM102 and SUM149 were more sensitive to GSI (IC50, 0.3 and 1.5μM, respectively) compared to the luminal MCF7 (>10μM) and HER2+ SKBR3 (>5μM) cell lines. Over 340 genes that changed in expression (FDR<0.03%) were identified in SUM102, including known targets of the canonical Notch pathway (Hes1 and Hey2). Selected GO terms overrepresented in this signature were the following (EASE score, p<0.01): Wnt and Hedgehog signaling, embryonic development and cell differentiation. In vivo, 2 distinct gene clusters were evident in both populations, one of which was predictive of poor patient outcome. This Notch-associated poor prognostic signature was highly expressed in >90% of basal-like tumors. The second cluster was highly expressed in the recently identified claudin-low subtype, and was uniquely enriched with genes involved in cell differentiation (Sox7/9, Hey2, Dll1, Fzd5) and cell adhesion. Conclusions: Notch associated expression profiles are associated with basal-like and claudin-low BC subtypes, providing additional biological insight of pathway activation. GSI could represent a novel strategy for both subtypes, which represent the vast majority of the “triple negative” population.

No significant financial relationships to disclose.