bluuebunny/crossref_metadata_2025 huggingface dataset:
Treatment of aggressive fibromatosis with pegylated liposomal doxorubicin: The Royal Marsden Hospital experience
Authors: Constantinidou A. , Scurr M. , Jones R. , Al-Muderis O. , Judson I.
Published: August 2020

10519

Background: Aggressive fibromatosis (AF) or desmoid tumors are monoclonal proliferations which are locally invasive but do not metastasise. Sporadic tumors are usually associated with mutations in the beta-catenin gene CTNNB1whereas those occurring in the context of familial adenomatous polyposis usually have inactivating mutations in APC. Histologically they are characterised by nuclear expression of beta-catenin. When surgery and radiotherapy are not applicable or fail to control the disease, systemic treatment with anti-oestrogens, non steroidal anti-inflammatory drugs (NSAIDs) and chemotherapy can be used. A variety of regimens are reported to have activity including methotrexate/vinblastine and doxorubicin/dacarbazine. Recent reports indicate that single agent pegylated liposomal doxorubicin (Caelyx, C) is also effective. Methods: Ten patients with AF received C between June 2006 and December 2008. C was administered intravenously at 50 mg/m2 over 1 hour every 4 weeks. Results: The female/male ratio was 9:1 and the median age at presentation was 39.5 years (range 18–53). All patients had progressive fibromatosis. Fifty percent had previously been treated with surgery/radiotherapy or both. All but one had previous systemic therapy which comprised tamoxifen/toremifene (6), NSAIDs (1), chemotherapy (1) and imatinib (1). C was well tolerated with mucositis (6/10), palmar-plantar erythema (4/10) and fatigue (2/10) being the main toxicities. A dose reduction to 40 mg/m2 was required in 50% of cases hence the optimal dose lies between 40 and 50 mg/m2. One patient is currently receiving treatment and is too early to assess. For the nine patients who have completed treatment the median number of C cycles was 6 (range 4–6). Objective response according to RECIST was achieved in 4/10 patients and in 5 patients the best response was stable disease. Clinical benefit (pain relief, improved mobility) was observed in all patients. The duration of response ranged from 4 to 28 months. Conclusions: This is the largest series of patients with AF receiving C presented to date. C as single agent therapy has acceptable toxicity and highly promising activity in unresectable AF and may provide long term clinical benefit in some patients.

No significant financial relationships to disclose.
An open-label multicenter phase II study of bevacizumab for the treatment of angiosarcoma
Authors: Agulnik M. , Okuno S. H. , Von Mehren M. , Jovanovic B. , Brockstein B. , Benjamin R. S. , Evens A. M.
Published: August 2020

10522

Background: The limited therapeutic options and dismal prognosis for patients (pts) with angiosarcomas (AS) provide a strong rationale for the evaluation of new therapies. Preclinical studies in AS tumor models have shown antitumor effects of antiangiogenic agents. We conducted a phase II study to determine the antitumor effect of bevacizumab in AS. Methods: The study was a two-stage design in which patients with newly diagnosed or relapsed/refractory AS and epithelioid hemangioendotheliomas were treated with bevacizumab 15 mg/kg IV every 3 weeks. Treatment was continued until progression or unacceptable toxicity. Response was assessed by RECIST criteria. Results: To date, of 29 pts enrolled, 28 received treatment. Baseline data on 29 pts are: M:F= 12:17 and median age 62 (range 18–94). Three pts are not evaluable (1 too early, 2 full treatment not given). Among 26 pts evaluable for response so far: 3 have PR (range 3–16 cycles), 13 have SD (3–32 cycles) and 10 have PD. ORR 3/26 (12%). After 141 cycles of therapy, only 1 grade 4 adverse event occurred (thrombocytopenia) and 5 patients experienced a grade 3 adverse event (anemia, pleural effusion, congestive heart failure, pain, headache, and nausea). Conclusions: Bevacizumab monotherapy for AS resulted in a response rate of 12% and tumor stabilization achieved by 62% of pts. Further studies with bevacizumab in combination with chemotherapy should be explored in this disease.

No significant financial relationships to disclose.
Phase II study of gemcitabine and docetaxel as first-line chemotherapy in locally advanced/metastatic leiomyosarcoma
Authors: Seddon B. M. , Scurr M. R. , Jones R. L. , Wood Z. , Propert-Lewis C. , A'Hern R. , Whelan J. S. , Judson I. R.
Published: August 2020

10528

Background: Locally advanced/metastatic soft tissue sarcoma is invariably incurable with a poor prognosis. Recently gemcitabine and docetaxel have been shown to be active in pre-treated relapsed leiomyosarcoma. This study aims to investigate the combination as first line treatment in patients with unresectable incurable leiomyosarcoma. Methods: Patients received gemcitabine 900mg/m2 days 1 and 8, and docetaxel 100mg/m2 day 8, administered 3-weekly for up to 8 cycles, with GCSF support on days 9–15. Patients who had received previous radiotherapy were treated at 75% dose. Patients were evaluated for response by RECIST after cycles 2, 4, 6, and 8, and three-monthly after completing treatment. The study was conducted with a Simon 2-stage design, recruiting 19 patients in stage 1, and 25 patients in stage 2. The primary endpoint was response rate, and secondary endpoints progression free survival (PFS), overall survival (OS), and toxicity evaluation. Results: Forty-four patients were treated. Eligible patients had histologically proven leiomyosarcoma of the uterus (48.9%) or other sites (51.1%) unresectable for cure, with measurable disease, no previous chemotherapy, adequate organ function, and performance status 0–2. 84.4% had metastatic disease, and 15.6% had locally advanced disease. 11% of patients had grade 1 disease, and 89% had grade 2/3 disease. All patients had demonstrated disease progression prior to trial entry. Responses were as follows: partial response 12 (27%), stable disease (confirmed) 16 (36%), stable disease (unconfirmed) 5 (11%), progressive disease 11 (25%). Median OS and PFS were 578 (95% CI 131–322) and 216 (95% CI 24–169) days. Progression free rates at 3 and 6 months were 68.9% (95% CI 55.1–82.7%) and 57.8% (95% CI 43.1–72.5%). Conclusions: This study demonstrates gemcitabine and docetaxel to be active in leiomyosarcoma in the first line setting. Further investigation comparing the combination with current standard therapies for leiomyosarcoma is warranted.

No significant financial relationships to disclose.
Utility of total body FDG PET/CT imaging in the initial staging of soft-tissue sarcoma
Authors: Roberge D. , Hickeson M. , Charest M. , Turcotte R. E.
Published: August 2020

10531

Background: Soft-tissue sarcoma spreads predominantly to the lung. It is currently unclear how often PET scan will detect metastases not already obvious by chest imaging or clinical examination. Methods: Soft-tissue sarcoma cases were identified retrospectively. Ewing's sarcoma, rhabdomyosarcoma and GIST tumors were excluded as were patients imaged for follow-up, response assessment or recurrence. Patients all had had a diagnostic chest CT scan as part of their staging. Directed studies were requested to follow-up on abnormal findings in the clinical history or physical examination. All charts and pre-treatment imaging were reviewed retrospectively. Results: From 2004 to 2008, 75 patients met the criteria for this review. These 75 patients had total body FDG-PET/CT imaging on routine initial staging of their sarcoma. The median age was 51. In 21% of cases, the primary tumor had been removed by excisional biopsy or unplanned excision prior to staging. 97% of the previously unresected primary tumors were FDG avid (SUV ≥ 2). 81% of tumors were high-grade (FNCLCC Grade 2–3). The primary tumor was stage T2b in 68% of cases. The most common primary site was the lower extremity (55%). The most common pathological diagnoses were: leiomyosarcoma (21%), liposarcoma (19%) and synovial sarcoma (17%). At the end of staging, 17% of patients were considered to have metastatic disease. PET scans were negative for distant disease in 64/75 cases. Seven of these 64 cases had metastatic disease on chest CT (negative predictive value 89%). 8 PET scans were positive - of these, 4 patients were already known to have metastases, 2 were pathologically proven false positives and 1 was a new finding of a pulmonary metastasis (sensitivity 46%). Three patients had indeterminate PET scans (subsequently none developed metastatic disease). Two incidental benign parotid tumors were found. In total, only 1 patient was upstaged by the PET imaging (1.3%). In addition, PET did not alter management of patients already know to have M1 disease (no new organ sites identified). Conclusions: Although PET scans may be of use in specific circumstances, routine use of FDG PET imaging for detection of metastatic disease as part of the initial staging of soft-tissue sarcoma adds little to chest CT scanning and is unlikely to alter management.

No significant financial relationships to disclose.
Adjuvant therapy with imatinib in gastrointestinal stromal tumor (GIST) patients with intermediate or high risk: Analysis from a single-center contrast study
Authors: Li J. , Gong F. J. , Li J. , Wu W. A. , Shen L.
Published: August 2020

10556

Background: Imatinib benefits the patients with metastatic GIST but whether it is effective in the adjuvant setting after complete tumor resection of primary GIST is questionable. Methods: Patients who had undergone complete tumor resection with intermediate or high risk of recurrence (define) were enrolled in a single-center non-randomized open contrast study. Patients had adjuvant therapy with imatinib (400mg once a day) for 3 years commencing within 12 weeks of tumor resection, or had follow-up alone. We performed c-kit and PDGFRA mutation analysis for patients with archival tumor samples. The primary objective was recurrence-free survival (RFS) and the second objective was correlation of gene mutation profile with efficacy of adjuvant therapy. Results: One hundred and five patients were enrolled: 56 patients in adjuvant therapy group and 49 patients in control group. Median follow-up was 30 months (range 12–62); Median treatment duration in adjuvant therapy group were 20 months (range 12–36); There was relatively higher 1-year and 2-year RFS in the adjuvant therapy group compared with the control group (100% vs 89.8%,94.4% vs 60.0%) (Log-RankP< 0.001). Hazard risk was 0.13 (95% CI 0.039–0.438, P= 0.001) in Cox proportional hazard regression model. For further sub-group analysis, Log-rank and Cox regression analysis showed that adjuvant therapy could significantly decrease recurrence risk in patients with high risk disease (define)(2-year RFS: 91.5% vs 46,2%, Log-Rank: P<0.001, HR:0.107 (95%CI 0.031–0.370), P<0.001). c-kit and PDGFRA mutation were analyzed in forty-nine patients. There was a better survival benefit from adjuvant therapy for patients with c-kit exon 11 mutation. Conclusions: Adjuvant therapy with imatinib can improve 1-year and 2-year recurrence-free survival for patients with an intermediate or high risk of recurrence after complete tumor resection.

No significant financial relationships to disclose.
KIT and PDGFRAmutation status and their immunohistochemical (IHC) expression profile of gastrointestinal stromal tumor (GIST) patients treated with imatinib (IMT): Seven-year single-center experience
Authors: Koh Y. , Kim H. , Lee H. , Lee K. , Oh D. , Kim J. , Im S. , Kim T. , Kim W. , Bang Y.
Published: August 2020

10558

Background: Previous studies suggested the role of KIT and PDGFRAmutations on treatment outcome of GIST with IMT, but results are heterogeneous. IHC value of PDGFRA and PDGFRB is not established. Methods: We included patients (pts) treated with IMT as a first line therapy for metastastic or relapsed GIST between 2001 and 2008. Tumor DNA was extracted to investigate the mutation status of KITexon 9, exon 11, PDGFRA exon 12 and 18. IHC stain of c-KIT and PDGFRA/B was performed. We assessed the correlation between the treatment outcome, genetic status and IHC results. Results: A total of 85 pts (M:F=49:36, median age 58.4 years) received IMT 400 mg daily. Location of primary disease included stomach (33), small bowel (34), rectum (10), esophagus (1), and omentum/mesentery (7). Complete and partial responses were achieved in 6% and 62% of pts respectively, while 5% of pts had progressive disease. During median follow up of 28.1 months, estimated median PFS was 39.8 months. KIT exon 11 and 9 mutations were detected in 64% and 5% respectively. Exon 11 mutations included 44 deletions, 2 insertions, 5 substitutions and 3 deletion/insertions. PDGFRA exon 12 and 18 mutations were detected in 2% respectively. Positive rate of c-KIT, PDGFRA and PDGFRB using IHC was 96%, 21%, and 26% respectively. PDGFRA and PDGFRB were co-expressed (p=0.001). PDGFRA mutation did not correlate with PDGFRA/B expression. Clinical response was not different according to the mutation status or IHC expression. PFS of KIT exon 11, KITexon 9, PDGFRA mutants and pts without detectable mutations were not different (p=0.397). Pts with KIT exon 11 balanced mutations (substitution or deletion/insertion) showed longer PFS compared with pts with unbalanced mutations (deletion or insertion) (p=0.014) or pts without exon 11 mutations (p=0.033). Median PFS was shorter in pts lacking c-KIT (p=0.001) expression. PDGFRA/B expression did not influence PFS. Conclusions: Balanced mutation of KIT exon 11 predicted longer PFS, while lack of c-KIT protein expression predicted shorter PFS for GIST pts treated with first line IMT. PDGFRA and B were co-expressed without predictive value.

No significant financial relationships to disclose.
Regulational effects of breast cancer stromal cells and normal breast stromal cells on MCF-7 mammosphere formation
Authors: Zhang F. , Xu Y. , Song C. , Ma Y. , Nan F. , Wang H. , Lin S. , Huang M. , Zhang Y.
Published: August 2020

1056

Background: It is well known that microenvironment plays an important role in tumor progression so we investigated the regulatory effects of breast cancer stromal cells (BCSCs) and normal breast stromal cells (NBSCs) as microenvironment on MCF-7 mammosphere formation. Methods: MCF-7 cells were cultured in suspension to generate mammospheres. The proportion of CD44+CD24- cells was assessed by flow cytometry and the expression of Wint1, notch1, β-catenin, CXCR4, SOX2, and ALDH3A1 was detected by real-time PCR. The stromal cells were purified and identified by immumohistochemistry. BCSCs or NBSCs and MCF-7 cells were co-cultured via Transwell system, the volumes and numbers of mammospheres and the mammosphere-forming efficiency (MFE) were calculated and the expression of Wnt1, β-catenin, Notch1 were detected. Results: The proportion of CD44+CD24- cells in mammospheres and MCF-7 cells was 10.4% and 2.1% (p < 0.05), respectively. Real-time PCR analysis suggested that Wint1, notch1, β-catenin, CXCR4, SOX2, and ALDH3A1 genes in the mammosphere cells were with higher levels than MCF-7 cells by about 2.25, 2.45, 1.72, 4.68, 4.25, 5.38 fold, respectively (p < 0.01). The stromal cells purified were identified as fibroblasts by α-SMA,Vimentin and fibroblast special protein antibody via immumohistochemistry. The time of mammosphere's formation was earlier, the volumes of mammospheres were bigger, and the MFE was higher than control group. The expressions of Wnt1 in co-culture group were significantly upregulated 1.27, 3.18 folds than control group, respectively, while the β-catenin was 1.22, 1.75 folds; Notch1 was 1.31, 2.09 folds; and CXCR4 was 1.73, 2.77 folds, respectively. Conclusions: Mammosphere cells contained higher propotion of breast cancer stem cells and expressed higher levels of cancer stem cell related genes. BCSCs can promote the mammosphere-forming efficiency and upregulate the expression of cancer stem cell related genes.

No significant financial relationships to disclose.
Response to sirolimus in combination to tirosine kinase inhibitors (TKI) in three cases of PDGFRA-D842V metastatic gastrointestinal stromal tumor (GIST)
Authors: Piovesan C. , Fumagalli E. , Coco P. , Palassini E. , Dileo P. , Morosi C. , Gronchi A. , Casali P.
Published: August 2020

10565

Background: In GISTs, specific KIT/PDGFRA mutations lead to differential drug sensitivity. The exon 18 PDGFRA-D842V mutation is known to be resistant to imatinib and sunitinib. Activation of tyrosine kinase receptor involves a signal transduction pathway involving AKT/mTOR, RAS, phosphoinositide 3-kinase and BRAF. We therefore used the mTOR inhibitor sirolimus in three pts with a PDGFRA-D842V metastatic GIST. Methods: Since August 2007, 3 PDGFRA-D842V GIST pts (age: 54–56–63 yrs) have been treated with sirolimus (2–3 mg/day) in combination to TKI (PKC412 in one pt, and imatinib in 2 pts), on an individual use basis. Two pts were progressing on imatinib, while the third pt was treated with imatinib + sirolimus upfront. Sirolimus blood levels were assessed. Results: Two pts had a Choi's response 6 and 3 mos, respectively, after starting the combination. In the first pt, responding to sirolimus + PKC412, the latter drug had been started alone, with no response. The last pt, undergoing imatinib + sirolimus, has a short follow-up. Disease was stable at 2 mos, although clinical improvement was noticed, and therapy is ongoing. The first pt underwent surgery of residual peritoneal disease after 13 mos, and is now continuing therapy being surgically NED. The other pt had a tumor progression after 9 mos from starting therapy and 6 mos from tumor response (with a negative PET scan). Treatment was relatively well tolerated, with skin toxicity in one pt. Conclusions: PDGFRA-D842V GIST are poorly responsive to TKI. We saw signs of antitumor activity in 3 pts with this mutation by combining TKI (imatinib or PKC412) with sirolimus. Tumor response was seen following some months of therapy. Studies are warranted.

[Table: see text]
registHER: Treatment outcomes in patients with HER2-positive (HER2+), hormone receptor-positive (HR+) metastatic breast cancer (MBC)
Authors: Tripathy D. , Kaufman P. , Brufsky A. , Mayer M. , Yood M. , Wang L. , Brammer M. , Yardley D. , Tan-Chiu E. , Rugo H.
Published: August 2020

1057

Background: Approximately 50% of HER2+ breast cancers are HR+ (defined as estrogen receptor [ER] and/or progesterone receptor [PR] positive). Cross talk between growth factor and ER-dependent signaling pathways may affect growth regulation in HER2+ breast cancers. Blockade of both pathways appears to be more active than blocking either alone based on randomized trials performed in selected populations. However, the outcomes of HER2+ and HR+ MBC patients relative to those in real- life clinical practice have not been evaluated in large cohort studies. Methods: registHER is a prospective observational study of 1023 patients with newly diagnosed (within 6 months [mo]) HER2+ MBC treated in community/academic settings, enrolled from 12/03 to 2/06. Median follow-up from MBC diagnosis was 25 mo at data cutoff (1/02/08). Treatment patterns and outcomes in patients with HER2+/HR+ MBC receiving 1st-line therapy (i.e., therapies received prior to 1st progression) are described in this analysis. Results: Of the 963 (94%) treated HER2+ patients with recorded HR tumor status, 55% (533) were HR+ and 45% (430) were HR-negative. 1st-line MBC treatment regimens for HER2+/HR+ patients included endocrine therapy (E) only, 57 (10.7%); E + trastuzumab (T), 50 (9.4%); chemotherapy (C) ± E, 41 (7.7%); and C + trastuzumab (T) ± E, 361 (67.7%). Progression-free survival (PFS) and overall survival (OS) by 1st line treatment groups are in the table. Conclusions: In registHER, HER2+/HR+ patients treated with E+T had longer PFS than patients treated with E alone; E- alone median PFS is consistent with findings in prospective randomized trials. These data provide further information regarding trastuzumab's role in targeting dual pathways in HER2+/HR+ MBC patients in a real-world setting. Multivariate analysis to address potential bias from known prognostic factors that may influence treatment choice will be presented.

[Table: see text]

[Table: see text]
Early results of a PMH Phase II Consortium trial of AZD0530 in advanced soft tissue sarcoma (STS)
Authors: von Mehren M. , Chu Q. , Alcindor T. , Townsley C. , Thallury S. , MacAlpine K. , Wright J. J. , Oza A.
Published: August 2020

10579

Background: AZD0530 is a novel oral anilino quinazoline that is selective for c-Src, c-Yes, Lck, and Bcr-Abl through ATP competitive and reversible inhibition of the target enzyme. Src kinases play a role in tumor cell migration, invasion and metastasis as well as being part of the signaling cascade for angiogenesis and growth factors. Advanced STS have limited therapeutic options; therefore we tested the efficacy of AZD0530 in advanced STS. Methods: The study utilized a Simon Two stage design with the primary endpoint be objective tumor response + prolonged stable disease rate (defined as partial/complete response by RECIST, or stable disease >4 months). Patients with measurable advanced STS with up to one prior chemotherapy for metastatic disease were eligible for study participation following informed consent. Patients were excluded for cardiac dysfunction, poorly controlled hypertension, inability to swallow or absorb medication. Patients had pulmonary function tests at baseline that were repeated within the first 4 weeks of therapy. Results: 17 patients (11 F, 6M) with advanced STS (leiomyosarcoma 5, rhabdomyosarcoma 3, MFH/carcinosarcoma/Fibrosarcoma 2, endometrial stromal sarcoma/liposarcoma/non-rhabdoSTS 1 each) were enrolled, the majority of whom had prior therapy (14 chemo and 9 xrt). Five continue on study. Nine discontinued therapy for progressive disease, 2 for toxicity and 1 patient request. Median time to progression in the 13 patients was 1.7 months. Possibly related severe adverse events (all grade 3) included fatigue (2), anemia/lymphopenia/hypokalemia (1 each). To date no confirmed responses have been seen. No drug related pulmonary toxicity has been observed. Conclusions: AZD0530 can be administered safely as a single agent in patients with a variety of advanced STS. To date, tumor responses have not been noted; however patients were not selected based on tumor target expression. Further testing may be warranted in selected tumors in combination with chemotherapy given pre-clinical synergy data or in tumors pre-selected for target expression.

No significant financial relationships to disclose.
Comparison of ER, PR, HER2 in primary and paired relapsed/metastatic lesions of metastatic breast cancer patients
Authors: Sari E. , Guler G. , Hayran M. , Altundag K. , Gullu I. , Ozisik Y.
Published: August 2020

1063

Background: The assessment of ER, PR and HER2 is made routinely in every breast cancer patient to have information about prognosis and to select patients (pts) who are candidates for hormonal and anti-HER2 therapy. Recent studies have shown some degrees of discordance in ER, PR, and HER-2 expression between primary and recurrent/metastatic lesions (RML). In this study we compared the ER, PR, and HER2 status of the primary and paired RML in metastatic breast cancer pts. Methods: Analysis was made on 79 metastatic breast cancer pts whose ER, PR, and/or HER2 status were known both on the tissue samples of primary and RML. ER, PR, and HER2 status were determined by immunohistochemistry and/or fluorescence-in-situ hybridization. Results: Among the RML sites, 24% were locoregional, 76% were distant metastatic sites. Among 72 pts with known ER expression on both primary and RML, 36% showed discordance on ER expression. Most of the change occurred from negative to positive ER status (15 of 48 ER positive primaries had ER negative paired metastasis and 11 of 24 ER negative primaries had ER positive paired metastasis). Among 68 pts with known PR expression on both primary and RML, 51.5% showed discordance on PR expression. Change in PR status from positive to negative and negative to positive was similar (23 of 45 PR positive primaries had PR negative paired metastasis and 12 of 23 PR negative primaries had PR positive paired metastasis). Among 58 pts with known HER2 expression on both primary and RML, 15.5% showed discordance on HER2 expression. Six pts with HER-2 negative primaries, showed HER2 overexpression in their paired RML. Four pts who had HER2 overexpressing primary did not show HER2 expression in the paired RML. Conclusions: A proportion of pts show discordances in hormonal receptor and HER2 expression between the primary tumor and the paired RML. As these discordant results make changes in treatment decision, a biopsy of the metastatic lesion could be recommended in metastatic breast cancer pts when feasible.

No significant financial relationships to disclose.
Brain metastases in breast cancer: Different survival by biological subtype and Ki67 expression
Authors: Sartori D. , Bari M. , Pappagallo G. L. , Rosetti F. , Olsen S. , Vinante O.
Published: August 2020

1069

Background: Ten to 15% of patients (pts) with breast cancer will be diagnosed with central nervous system (CNS) metastases, and autopsy series suggest that up to 30% of pts have evidence of CNS disease at the time of death. The idenfication of factors that may predispose to CNS metastasis may help lead to earlier detection and possibly to improvement in disease management. Methods: Breast cancer pts with CNS metastases were identified within a database of 1300 breast cancer diganoses from 1995 to 2007 at the Department of Oncology, Azienda ULSS 13 VE. Pathologic features of tumor samples were examined using standard immunohistochemical assays. Results: Fifty-one pts with CNS metastases were identified. Median age at primary breast cancer diagnosis was 49 years (range, 28–78); median time to CNS metastases was 45 months (range, 3–244). HER2 overexpression was found in tumors from 25 pts (49.0%); 23 pts had tumors lacking overexpression of HER2, estrogen receptors (ER), and progesterone receptors (PgR) (ie, “triple negative” disease). Overexpression of p53 (at least 20% tumor cells positive), Ki67 (at least 20%), and BCL2 (at least 30%) were detected in tumors from 16 pts (31.4%), 32 pts (62.7%), and 14 pts (27.5%), respectively. Median survival from CNS involvement was 3.67 months (95% CI 2.05–5.28), with 24.4% and 15.3% of patients estimated to be alive at 12 and 24 months, respectively (Kaplan-Meier product limit method). A Cox proportional hazards analysis found that Ki67 overexpression was the only factor independently associated with a significantly increased risk of death (2.7-fold increase, p=0.028), while triple negative status was associated with a 1.8-fold increase in the risk of death (P=0.08) (Table). Conclusions: In our series of breast cancer pts with CNS metastases, nearly all had either HER2 overexpression or triple-negative disease. Pts whose tumors had higher proliferative indices, assessed by Ki67, had the poorest prognosis.

[Table: see text]

[Table: see text]
Differential timing and patterns of recurrence among breast cancer subtypes
Authors: Scruggs K. V. , Pradhan S. M. , Mfalila C. , Moore D. , Burrows E. , Drobish A. , Carey L.
Published: August 2020

1076

Background: At present, effects of heterogeneity among breast cancer subtypes on timing and patterns of relapse are not fully understood. We characterized timing and patterns of distant recurrence among subtypes in women followed from initial diagnosis of breast cancer. Methods: 345 pts with newly diagnosed predominantly stage II-III breast cancer were treated with multiagent neoadjuvant therapy and subtyped by IHC: LumA (ER/PR+, HER2-); LumB (-ER/PR+, HER2+); Basal (triple neg); HER2 (HER2+,ER/PR-). Site-specific patterns of distant metastasis (DM) were examined among pts with single site of first DM. Sites of relapse were bone, CNS, viscera, lymph node, and soft tissue. Time to progression (TTP) was from date of initial diagnosis. Results: 108 patients developed metastatic disease; 65 demonstrated a single site of first DM. Basal subtype was associated with greater CNS and visceral metastases and fewer bone metastases than other subtypes. LumA subtype was associated with fewer CNS and greater bone metastases than other subtypes. [See table]. Dichotomizing as Basal v. non-Basal, bone v. no bone and CNS v. no CNS revealed identical trends with increased significance (p=0.01–0.03). TTP trended toward Basals demonstrating earliest DM and LumA latest. Excluding pts with DM at diagnosis, TTP differed between Basals and non-Basals within viscera (p=0.002, n=14/21, median TTP=10/21); CNS (p=0.047, n=8/7, median TTP=11/27); and bone (p=0.002, n=8/31, median TTP=9/21). Conclusions: Subtypes exhibit distinct timing and patterns of relapse within this largely homogeneous cohort of pts with predominantly locally advanced breast cancer, despite modern multiagent neoadjuvant therapy. Specifically, Basal cancers exhibit earlier recurrence and greater involvement of sites more difficult to treat than non-Basals. Within individual sites TTP differences between Basal and non-Basal tumors persist and are even more pronounced, suggesting that tumor microenvironment does not appear to be driving these differences.

[Table: see text]

No significant financial relationships to disclose.
Phase I trial of panobinostat (LBH589) in combination with trastuzumab in pretreated HER2-positive metastatic breast cancer (mBC): Preliminary safety and tolerability results
Authors: Conte P. , Campone M. , Pronzato P. , Amadori D. , Frank R. , Schuetz F. , Rea D. , Wardley A. , Britten C. , Elias A.
Published: August 2020

1081

Background: Panobinostat is a potent inhibitor of histone deacetylase (HDAC) and has demonstrated single-agent activity and synergistic effects in combination with trastuzumab or docetaxel in HER2 positive BC xenografts. Methods: Previously treated mBC patients (pts), who progressed on or within 6 months of trastuzumab-based therapy, were enrolled in this multicenter study. Pts were dosed with either i.v. (Day 1+8) or oral panobinostat (three times per week, continuously) every three weeks in combination with standard weekly dose trastuzumab. To establish maximum tolerated dose, three (10, 15, and 20 mg/m2) and four (15, 20, 30 and 40 mg) cohorts are planned for treatment with i.v. and oral panobinostat, respectively. The pharmacokinetic (PK) profile is also measured. Results: Eighteen pts have been enrolled in this ongoing trial. Median age 54 yrs (33–60). Six pts were ER and PR negative, eight pts had liver metastasis, eight pts had lung metastasis, and two pts had central nervous system metastasis. All patients received prior taxanes and/or anthracyclines. All progressed on or within 6 months of trastuzumab-based treatment. The first cohort completed accrual with 13 pts (seven received oral and six received i.v. panobinostat). No dose-limiting toxicity (DLT) was reported in the i.v. arm, and only one DLT, uncomplicated grade 4 thrombocytopenia, was reported in the oral arm. The second cohort is ongoing, eight pts have been enrolled (five in i.v. and three in oral), and no DLTs have been reported yet. Additional safety results include: one pt with grade 3 leucopenia and grade 1 or 2: nausea in six pts; vomiting, four pts; diarrhea, five pts; stomatitis, three pts; and fatigue, three pts. One pt had grade 2 asymptomatic QT prolongation. In the first cohort, two pts experienced tumor reduction of 29% (both had liver metastasis), and four pts received over eight cycles of the combination. Conclusions: The preliminary results in the first cohort demonstrated that the combination is well tolerated and shows promising activity. Additional patient safety and full PK data will be presented.

[Table: see text]
Cardiac safety of the lapatinib/letrozole combination as first-line therapy in patients (pts) with metastatic breast cancer (MBC)
Authors: Zembryki D. , Gomez H. , Koehler M. , Koehler M. , Johnston S. , Pippen J. , Florance A. , O'Rourke L. , Maltzman J. , Pivot X.
Published: August 2020

1095

Background: Cardiotoxicity of traztuzumab therapy increases in pts pretreated with anthracyclines (A), radiotherapy to left breast, hypertension, or low baseline ejection fraction (EF). We report the cardiac safety profile of lapatinib, an oral, dual EGFR/HER-2 tyrosine kinase inhibitor, in a chemotherapy naïve or A-exposed pts with MBC. Methods: Women (n = 1286) with endocrine sensitive, previously untreated MBC received lapatinib and letrozole (L+L) or letrozole and placebo (L+P): 33% received previous A; 48% previous tamoxifen; <1% previous trastuzumab (T); <2% previous aromatase inhibitor. EF was evaluated by MUGA or echocardiogram at baseline, every 8 wk and at study withdrawal. Rate of cardiac events (NCI CTCAE grading), median time to onset, and duration of EF depression were assessed. Results: Cardiac events (CE; MEDRA terms: ejection fraction decreased, left ventricular dysfunction, ventricular dysfunction and cardiac failure) were infrequent in both arms. Grade 3/4 and 1/2 CE were reported in 0.9% and 4.0% of pts, respectively, in the L+L arm, and in 0.3% and 2.1%, respectively, in the L+P arm. The only symptomatic CE was a grade 4 event in the L+L arm. There was no apparent relationship between previous A exposure and CE frequency and severity. Median L exposure was 40 wk on L+L, 38 wk on L+P. Median time to onset and duration of EF decrease were 21.8 and 8.1 wk, respectively, on L+L, and 34.6 and 5.4 wk, respectively on L+ P. On the L+L arm, the dose was adjusted/interupted for 8 CE cases, discontinued for 6, and unchanged for 22. On the L+P arm, interuption of L was reported for 2 CE cases, discontinuation for 5, and in 7 CE events there was no change in therapy. Eight CE on L+L and 1 CE on L+P had not resolved as of the last report. Conclusions: This is the first long-term evaluation of lapatinib cardiac signals in a controlled trial in a trastuzumab-naïve MBC pt population. The frequency of cardiac events and degree of absolute EF decrease was low and occurred at similar rates in pts with or without anthracycline exposure. These encouraging cardiac safety data in first line metastatic BC study are promising for the ongoing study of lapatinib in patients with early HER-2+ BC treated on ALTTO trial.

[Table: see text]
The effect of age on overall survival (OS) in patients with metastatic breast cancer (MBC) treated with capecitabine
Authors: Blum J. L. , Hu X. , Odom D. , Sherrill B. , Glück S.
Published: August 2020

1097

Background: Both in monotherapy and in combination with a taxane, C has been shown to improve OS in patients with MBC. Since C is often used in older adults because of tolerability and ease of administration (PO vs IV), and lack of alopecia, an exploratory analysis was conducted to see if an association exists between age and OS among patients with MBC treated with C. Methods: Data from the intermittent dose (2510 mg/m2) 2 wks on/1 wk off arms of 5 phase II/III monotherapy or combination therapy with C registration trials involving patients with MBC were analyzed. Intent-to-treat (ITT) was defined as all randomized patients who took at least 1 dose of study medication. Patients were divided into 3 groups by age. A Kaplan-Meier method was used to estimate the age-category specific survival by trial. Next, Cox proportional hazard regression analysis was conducted using pooled data from the 5 trials with stratification by trial and key baseline characteristics. Analyses were conducted at the 95% confidence level. Results: A total of 570 ITT patients were included in the analysis (median age 55.0 years; range, 26–83): 193 (34%) were 18–49 years old; 246 (43%) 50–64 years old; and 131 (23%) ≥65 years old. A baseline Karnofsky score ≥90 was observed in 65.3%, 56.5%, and 50.4% of patients, respectively. The median treatment duration (range) was 93.0 (2–397) days in the 18 to 49-year-old group, 109.5 (2–448) days in the 50 to 64-year-old group, and 80.0 (5–371) days in the ≥65-year-old group. Unadjusted log-rank tests for each of the 5 trials showed no significant differences in OS between age categories. In the pooled analysis, Cox regression did not detect significant differences in survival based on age. Using age ≥65 years as the reference group, the hazard ratios were 1.06 (95% CI 0.81, 1.41) for age 18–49 years and 0.99 (95% CI 0.77, 1.29) for age 50–64 years. The Cox model revealed consistent results after further controlling for the Karnofsky score and number of metastatic sites. Conclusions: No statistically significant effect of age on OS was observed in patients with MBC treated with C. OS outcomes appear comparable across predefined age groups of patients with MBC treated with C.

[Table: see text]
Identification of candidate biomarkers of therapeutic response to docetaxel in hormone-refractory prostate cancer by proteomic profiling
Authors: Horvath L. , Zhao L. , Lee B. , Brown D. , Molloy M. , Marx G. , Boyer M. , Breit S. , Sutherland R. , Henshall S.
Published: August 2020

11010

Background: Docetaxel (DTX)-based chemotherapy improves symptoms and survival in men with advanced hormone-refractory prostate cancer (HRPC). However, approximately 50% of patients do not respond to DTX but are exposed to significant toxicity without direct benefit. This study aimed to identify novel therapeutic targets and predictive biomarkers of DTX-resistance in HRPC. Methods: Protein profiling using iTRAQ mass spectrometry compared the PC3-Rx and DTX-sensitive PC3 cells and DTX-resistant PC3-Rx developed by DTX dose-escalation. Functional validation experiments were performed using recombinant protein treatment and siRNA knockdown experiments. Plasma/serum samples were collected from 41 men with metastatic HRPC treated with DTX-based chemotherapy (36 with paired samples pre- and post- cycle 1 DTX). Serum/plasma levels of MIC-1 were measured by ELISA. The association between MIC-1 levels, PSA response and overall survival (OS) were assessed by non-parametric tests and Kaplan-Meier survival analysis. Results: The IC50 for DTX in PC3-Rx was 10-fold higher than that in parent PC-3 cells. Protein profiling identified that MIC-1 levels were elevated 2.4 fold and AGR2 decreased 2.4 fold in DTX resistant cells. Knockdown of AGR2 expression in PC3 cells resulted in increased DTX resistance (p=0.03). PC-3 cells treated with recombinant MIC-1 also became resistant to DTX (p=0.001). Conversely, treating PC3-Rx cells with MIC1-siRNA restored sensitivity to DTX (p=0.002). In HRPC patients, pre-treatment MIC-1 levels did not correlate with PSA response to treatment (p=0.6). In contrast, increased serum/plasma levels of MIC-1 after cycle one of chemotherapy were associated with DTX resistance (p=0.006) and shorter overall survival (p=0.002). Conclusions: These results suggest that both AGR2 and MIC-1 play a role in DTX resistance in HRPC. Furthermore, changes in serum/plasma MIC-1 levels are associated with DTX resistance in a correlative human cohort. While a larger study is needed to validate these findings, the data provide evidence that MIC-1 as a potential predictive biomarker and both MIC-1 and AGR2 are potential therapeutic targets in DTX resistance.

No significant financial relationships to disclose.
Nanoscale analysis of changes in signaling proteins in patients treated with single agent atorvastatin for low-grade or refractory NHL
Authors: Fan A. C. , Orban M. W. , Shirer A. E. , Rajwanshi R. , Kong C. , Natkunam Y. , Lee H. E. , Coutre S. , Felsher D. W.
Published: August 2020

11011

Background: In preclinical studies using our transgenic lymphoma model, lymphoma regression upon atorvastatin treatment was associated with increased apoptosis and changes in phosphorylation of key signaling pathways including MAPK and STAT. To determine if statins affect tumor signaling in patients, we designed a single arm phase II study, “Atorvastatin in Patients with Low Grade or Refractory Non-Hodgkin's Lymphoma.” Methods: Patients received 80 mg atorvastatin daily and underwent tumor sampling and PBMC collection by fine needle aspiration (FNA) and blood draw on days 1 and 8. The primary endpoint was to measure a 50% increase in tumor apoptosis on treatment day 8 compared with day 1. To characterize changes in protein profiles, we have developed the use of a novel nano-immunoassay system (NIA) to simultaneously measure both phosphorylated and unphosphorylated protein isoforms. NIA and multi-color flow cytometry were used to evaluate intracellular signaling protein profiles for each patient's tumor cells, monocytes, and T cells. Results: All 14 patients have completed treatment. The primary endpoint was reached in 9 of 14 patients with 50% increase in apoptosis. We distinguished three patterns of signaling changes. First, as expected, pathways that were initially activated in tumor cells decreased upon treatment with atorvastatin, with up to a 70% decrease in phospho-STAT3 and phospho-STAT5. Second, pathways that were initially suppressed in tumor cells (including phospho-PLCγ), normalized upon treatment. Third, expression levels of proteins in apoptotic pathways, including p38, increased upon atorvastatin treatment. Finally, changes in signaling associated with atorvastatin are cell specific: effects on tumor cells were distinct from effects on non-tumor T cells and monocytes. Conclusions: Single agent atorvastatin has a measurable effect on tumor bioactivity in patients with lymphoma. NIA and multi-color phosphoFACS can be used to monitor changes in cell signaling in very small clinical samples during therapeutic interventions. Determining whether specific signaling molecules may be a biomarker for identifying lymphoma patients that respond to atorvastatin is worthy of further investigation.

[Table: see text]
TGF-α and amphiregulin levels in non-small cell lung cancer (NSCLC) patients (pts) treated with erlotinib/placebo in the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) BR.21
Authors: Goss G. D. , Addison C. , Shepherd F. , Seymour L. , LeMaitre A. , Ding K.
Published: August 2020

11023

Background: In BR.21, erlotinib prolonged survival of previously treated NSCLC pts. We examined the predictive/ prognostic effects of the EGFR ligands, TGFa and amphiregulin(Am). Methods: Plasma was collected prior to treatment in consenting pts. TGFa and Am were analyzed by ELISA (R&D Systems). Samples were blinded, measured in duplicate and ligand concentrations determined following interpolation of a standard curve generated from known quantities of recombinant proteins. Sensitivity was ∼3pg/ml. Cutoff points for TGFa were <10 (low) and ≥10 (high); for Am <1.5 (low) vs 1.5–10 (intermediate) vs >10 (high). Standard statistical methods were used to correlate biomarker data with baseline characteristics and outcomes. Results: In 731 randomized pts, 539 were evaluable for both markers; there was a significant interaction (p=0.03) between the evaluable and inevaluable cohorts (erlotinib benefit favoring the evaluable cohort); evaluable pts were more likely to be male, > 60 and to have EGFR amplification. Baseline high TGFa was associated with poorer ECOG PS (p=0.03) while high Am was associated with worse PS (p<0.0001), anemia (p<0.0001), non response to prior therapies (p=0.01) and no-prior platinum therapy (p=0.02). Although TGFa was not prognostic for OS (HR=1.0, p=0.99), high Am was (HR: Middle vs low: 0.94, 95% C.I 0.49 -1.81; high vs.low: 2.04, 95% C.I 1.43 - 2.91; p=0.0002). High TGFa was a poor prognostic factor for PFS (HR 1.4, p=0.07) as was elevated Am (HR: Middle vs low: 1.02, 95% C.I 0.56 -1.85; high vs. low: 1.67, 95% C.I 1.19 - 2.35, p=0.01). In multivariate analyses including both ligands, high Am remained prognostic, but neither ligand was predictive. Conclusions: High levels of baseline Am appears to be a poor prognostic factor, while low levels of TGFa showed a trend to predict benefit from erlotinib in univariate analyses. [Table: see text]

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Skp2, a prognostic marker and potential therapeutic target in metastatic melanoma
Authors: Wang G. , Hanniford D. , Rose A. , Gaziel A. , Pavlick A. , Zhou X. , Wang J. , Pagano M. , Hernando E. , Osman I.
Published: August 2020

11034

Background: Skp2, a known oncogene, is overexpressed in several types of tumors and is associated with worse recurrence rate and overall survival in primary melanoma patients. Moreover, the anti-proliferative effects of Skp2 siRNA on various tumor cell lines have prompted the preclinical testing of Skp2 small molecule inhibitors. In this study, we assessed the clinical relevance and molecular mechanism(s) underlying Skp2 overexpression in metastatic melanoma patients. Methods: Skp2 protein levels were measured in 122 metastatic melanoma specimens using immunohistochemistry (IHC), and the association between Skp2 overexpression and post-recurrence survival was examined. Moreover, 22 cell lines (2 normal primary melanocytes, 2 primary immortal melanocytes, 4 primary melanoma cell lines, and 18 metastatic melanoma cell lines) were evaluated for Skp2 genomic amplification using Single Nucleotide Polymorphism (SNP) arrays (Affymetrix 6.0) and Skp2 gene expression using mRNA arrays (Affymetrix U133A 2.0) and quantitative RT-PCR. We also screened 18 cell lines for Skp2 mutation by sequencing. Results: Skp2 overexpression, defined as >25% tumor cells, was associated with shorter 3-yr post-recurrence survival (37%) compared to Skp2 expression ≤25% (55%) (HR=1.89, 95%, CI= 1.04, 3.42, p=0.04). Skp2 overexpression was significantly associated with the site of melanoma metastasis: visceral (n= 12; 89%), lymph node (n=49; 36%), brain (n=15; 14%), and soft-tissue (n=36; 6%) (p<0.001). SNP array revealed genomic amplification at the Skp2 locus in 6 (33%) metastatic cell lines and one primary melanoma cell line. Skp2 genomic amplification was associated with increased transcript expression. No Skp2 mutations were identified. Conclusions: Skp2 protein overexpression is associated with worse prognosis in metastasis in melanoma. Our results also support that gene amplification, rather than a Skp2 gene mutation, may be the major mechanism responsible for Skp2 aberrant expression in metastatic melanoma.

No significant financial relationships to disclose.
Identification of tumor tissue origin by a microRNA-based molecular assay
Authors: Rosenwald S. , Gibori H. , Gilad S. , Cohen L. , Leizerman I. , Barshack I. , Nonaka D. , Tobar A. , Aharonov R. , Rosenfeld N.
Published: August 2020

11036

Background: Hundreds of thousands of patients are diagnosed each year with metastatic cancer. For ∼10% of these, the tumor primary site is never identified, and they are defined as Cancer of Unknown Primary (CUP). Identification of tumor tissue-of- origin has significant therapeutic implications and presents a major diagnostic challenge. In previous work we showed that by combining expression profiles of tissue-specific microRNAs with a biologically-motivated classification scheme, tumor tissue-of-origin can be identified with high accuracy. Here we describe the development of this approach into a practical diagnostic assay. Methods: We developed protocols for extraction of high-quality RNA that retain the microRNA fraction from FFPE archival tissue samples. Proprietary, highly specific qRT-PCR was used to profile microRNA expression levels in hundreds of samples. Results: A training set of nearly 400 primary and metastatic tumors samples with known primary sites, representing 25 different tumor types, was used to define a standardized diagnostics assay (miRview mets). The assay uses a qRT-PCR protocol to measure a panel of 48 microRNA biomarkers. The assay was validated on a test set of nearly 200 primary and metastatic tumors whose primary sites were blinded. The classification protocol identifies either a single, high-confidence origin or two possible low-confidence predictions. Overall, correct primary site was identified for 83% of the tumors. For 70% of the cases a single high-confidence prediction was made; these cases had a higher accuracy: 90% of the primary sites predicted with high confidence were accurately identified. Conclusions: Previous studies highlighted the tissue-specificity of microRNA expression. We developed this potential into a diagnostic assay that identifies tumor origins with high accuracy. This assay provides an important new tool for diagnosing tumor tissue origin.

[Table: see text]