bluuebunny/crossref_metadata_2025 huggingface dataset:
Are all stage III Wilms tumors the same? Data from the Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP)
Authors: Spreafico F. , Piva L. , D'Angelo P. , Terenziani M. , Collini P. , Gandola L. , Bianchi M. , Tamburini A. , Provenzi M. , Fossati Bellani F.
Published: August 2020

10030

Background: Criteria to classifying Wilms tumor (WT) as stage III are much heterogeneous, including factors referring both to tumor biology and surgical skills. Methods: We analyzed survival results in patients aged less than 18 years with stage III WT enrolled in the AIEOP CNR92 and TW2003 clinical trials (10/1991–10/2008). Main therapy differences across the trials were the timing of abdominal radiotherapy (RT) (anticipated to 2nd week from nephrectomy) and doxorubicin cumulative dose reduction from 360 mg/m2 to 240 in TW2003. Results: Of 553 in-study patients, 106 (19%) were classified as stage III according to NWTS4 criteria (59 patients in CNR92, 47 in TW2003; median age 49 months). Reasons for stage III as follows: lymph nodes (LN) 40 cases (alone 28 cases, combined with other factors 12); cava vein tumor thrombus 7, peritoneum involvement 8, post-operative gross or microscopic tumor remains 24, pre-operative rupture 9, surgical rupture 17. For 29 patients (27%) information on regional LN were missing. 36 patients received primary 4-week vincristine/dactinomycin regimen, while the others had up-front nephrectomy. Adjuvant therapy consisted of 8-months vincristine/dactinomycin/doxorubicin + flank 1440 cGy RT (whole abdominal 15 Gy in case of diffuse peritoneal contamination). 7 patients had intensified chemotherapy/RT for diffuse anaplasia. Interval between nephrectomy and RT was 75 days in CNR92 (median) and 33 in TW2003. Overall 16 tumor failure occurred (2 in anaplastic tumors): abdominal relapse 8 (combined to other extra-abdominal site 3), lung 5, tumor progression 2, metacronous tumor 1. After median follow-up of 49 months 5-year RFS and OS were 83% ±4 and 90% ±3 for the whole cohort of children, respectively. Noteworthy the doxorubicin dose reduction in TW2003 did not jeopardize survival (82% 4-year RFS for CNR92, 84% TW2003). Overall, RFS was 75% ±7 in patients with at least LN involvement compared to 89% ±4 in patients classified as stage III for the remaining criteria, including those without LN sampling (Logrank p.09). Conclusions: The sensible doxorubicin dose reduction did not jeopardize survival. 1440 cGy flank RT warranted satisfactory local tumor control. The worse outcome reported in LN-positive patients deserves further attention.

No significant financial relationships to disclose.
Differences in length of stay among hospitalized children with acute lymphoblastic leukemia
Authors: Tai E. , Richardson L. , Townsend J. , Steele B.
Published: August 2020

10044

Background: Acute lymphoblastic leukemia (ALL) is the most common malignancy among children in the United States. While age, race, and clinical complications have been associated with longer length of stay (LOS) among children with cancer, it is unknown what factors are related to LOS among children with ALL. We examined differences in LOS among hospitalized children with ALL. Methods: We used 2000, 2003, and 2006 data from the Healthcare Cost and Utilization Project (HCUP) Kids’ Inpatient Database (KID) which contains pediatric discharges from community, non-rehabilitation hospitals. We used negative binomial regression to determine factors related to LOS. Results: We found the following factors related to greater LOS among hospitalized children with ALL: Non-Hispanic blacks vs. non-Hispanic whites (Rate Ratio (RR) = 1.06, CI:1.03–1.10), Hispanics vs. non-Hispanic whites (RR = 1.07, CI:1.04–1.10), age < 1 year vs. age 1–5 years (RR = 1.93, CI:1.83–2.04), female vs. male (RR = 1.05, CI:1.03–1.07), lowest quartile of household income in patient's zip code vs. highest quartile (RR = 1.09, CI:1.06–1.12), Medicaid vs. private insurance (RR = 1.11, CI:1.09–1.14), children's hospital vs. non-children's (RR = 1.11, CI:1.08–1.14), Western region of United States vs. Northeast region (RR = 1.14, CI:1.11–1.17), emergency room admission vs. routine admission (RR = 1.23, CI:1.20–1.26), blood transfusion (RR = 1.64, CI:1.61–1.67), bone marrow transplant (RR = 7.64, CI:7.11–8.20), and neutropenia (RR = 1.22, CI:1.19–1.24). Conclusions: Race/ethnicity, age, sex, household income, insurance status, admission source, hospital type and region, transfusion, bone marrow transplant, and neutropenia were significantly associated with longer LOS. These factors may help identify children with ALL at risk for complications. Prophylactic treatment for clinical complications may reduce LOS.

No significant financial relationships to disclose.
Result of adolescent acute lymphoblastic leukemia protocol (MCP 841) from a developing country
Authors: Mukhopadhyay A. , Gupta P. , Mukhopadhyay S. , Dey S. , Basak J. , Pandey R.
Published: August 2020

10046

Background: Acute Lymphatic Leukemia is a curable disease in the range of 80 - 90% in developed countries by aggressive protocol like BFM, St. Judes’ but result is much less in adolescence age group (60–70%). In developing countries like ours, patients can't tolerate that aggressive protocol because of socio-economic and nutritional factors. The less aggressive protocol like MCP841 is suitable in developing countries like ours. The aim of our study was to see outcome of adolescent ALL patient with protocol MCP 841 and tolerability of the protocol in Indian-Asian population. Methods: We treated 75 children with age range 13 - 18 years (median age of 15 yrs) with MCP 841 Protocol at Netaji Subhash Chandra Bose Cancer Research Institute, Kolkata, India, a tertiary cancer center from Eastern India during the period of April 1999 to Dec 2007. There was female preponderance in the study. Fever 48 (64.0%), lymphadenopathy 35 (46.7%), and haepatosplenomegaly 28 (37.3%) were the major clinical presentation. Eight (10.7%) patients were present with hyper leukocytosis. T-ALL phenotype was the largest group though the incidence of the C-ALL was quite high 23 (30.7%). Results: Remission induction was seen in 65 (86.7%) of the patients. In a follow-up period of 24 - 88 months (with an average of 54 months) the disease-free survival ( DFS) was 42 (56%) patients with an overall survival of 46 (61.34%) patients. The isolated bone marrow relapse was seen in majority of the cases 28 (37.34%) and the major relapse was in maintenance and first 6 months of completion of therapy. The major cause of morbidity was infection 53 (70.7%) followed metabolic complications 16 (21.34%), pancreatitis 3 (4.0%), hemorrhage 10 (13.3%), neurologic 2 (2.7%), and hepatitis 1 (1.3%). The major cause of the mortality was infection 18% (24.0% patients) followed progressive disease 9 (12.0%) and hemorrhage 2 (2.7%). As compared to our all pediatric ALL group the outcome is much less and complications are much more. Conclusions: The data of acute lymphatic leukemia in adolescent is not satisfactory as compared to other pediatric patients. They also tolerate chemotheraphy badly. Therefore there is need for modified protocol for this age group.

No significant financial relationships to disclose.
Efficacy and tolerability of imatinib mesylate in pediatric chronic myeloid leukemia in a large cohort: Results from a tertiary care referral center in India
Authors: Ghadyalpatil N. , Banawali S. , Kurkure P. , Arora B. , Bansal S. , Amare P. , Choughule A. , Soy L. , Singh R.
Published: August 2020

10047

Background: Chronic myeloid leukemia (CML) is a rare disease in children and there is limited data of safety and efficacy of imatinib mesylate (IM) in this age group. Methods: We analyzed the outcomes of 48 consecutive children (September 1998 to December 2008) in chronic phase (CP) or accelerated phase (AP) CML not eligible for Allo-SCT and were treated with IM [Glivec (Novartis), through patient assistance programme GIPAP or Veenat (NATCO), generic brand for GIPAP ineligible patients] within 12 months of diagnosis. The dose of IM was 260 mg/m2(maximum 400 mg) per day. Results: The median age at the time of diagnosis was 12 years (range 3–18 years). Of 48 patients, (34 males and 14 females) 46 were in CP and 2 in AP. Forty-three patients (89.5 %) achieved complete cytogenetic response (CCR) at median time of 10 months (range 3–31 months). Five patients (10 %) had hematological response but did not have CCR, of which 2 progressed to AP and 1 had hematological relapse. One patient had secondary IM resistance and had progressive disease even on dose escalation. Two patients in AP at diagnosis achieved CCR at 5 and 7 months and continue to be in CCR. Thirty-one out of 35 patients on Glivec and 12 out of 13 patients on Veenat achieved CCR. At a median follow up 29 months, the event free survival and overall survival was 74.1% and 100 % respectively. IM was well tolerated with grade III and IV neutropenia and thrombocytopenia seen in 2 and 7 patients respectively. Significant non hematological toxicities were uncommon except for hypopigmentation which was seen in more than half the cohort. Conclusions: Results from this largest single center study indicate that outcome of children with CML receiving IM is similar to adults. This data will be especially useful for financially challenged patients in developing countries where Allo-SCT is still not an affordable option while generic brand of IM seems to be feasible alternative.

No significant financial relationships to disclose.
RIBBON-1: Randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab (B) for first-line treatment of HER2-negative locally recurrent or metastatic breast cancer (MBC)
Authors: Robert N. J. , Dieras V. , Glaspy J. , Brufsky A. , Bondarenko I. , Lipatov O. , Perez E. , Yardley D. , Zhou X. , Phan S.
Published: August 2020

1005

Background: B in combination with weekly paclitaxel or docetaxel (D) as 1st-line therapy for MBC has improved progression-free survival (PFS) compared with the respective taxane alone in two large Phase III trials. This study investigated the addition of B to standard 1st-line chemotherapy regimens for MBC. Methods: Patients were randomized in 2:1 ratio to receive B + chemotherapy or placebo (pl) + chemotherapy. Prior to randomization, investigators chose capecitabine (Cap) (2000 mg/m2 x 14d), taxane (T) (nab-paclitaxel [260 mg/m2] or D [75 or 100 mg/m2], q3wk), or anthracycline (Ant)-based chemotherapy (q3wk). B or pl was administered at 15 mg/kg q3wk. Key eligibility criteria included MBC or locally-recurrent disease, no prior cytotoxic treatment, ECOG PS 0 or 1, HER2-negative disease and no CNS metastases. The primary endpoint was investigator-assessed PFS. Secondary endpoints included overall survival (OS), objective response rate (ORR), independent review of PFS, and safety. At progression, all patients were eligible for B with 2nd line chemotherapy. The Cap cohort and the pooled T or Ant (T + Ant) cohort were independently powered and analyzed in parallel using two-sided stratified log-rank test (Cap: 80% power to detect HR=0.75; T + Ant: 90% power to detect HR=0.7). Results: RIBBON-1 enrolled 1237 patients (Cap, 615; T, 307; Ant, 315) from 12/05 to 8/07 in 22 countries with a median follow-up of 15.6 months in the Cap cohort and 19.2 months in the T + Ant cohort. The results are summarized below. OS data are limited with only 33% of events. Safety was consistent with results of prior B trials. Conclusions: The addition of B to Cap, T; or Ant-based chemotherapy regimens used in 1st-line treatment of MBC resulted in statistically-significant improvement in PFS with a safety profile comparable to prior Phase III studies.

[Table: see text]

[Table: see text]
The economic implications of rasburicase treatment in pediatric tumor lysis syndrome patients
Authors: O'Day K. , Eaddy M. , Seal B. , Tangirala K. M.
Published: August 2020

10050

Background: Rasburicase is a recombinant urate-oxidase enzyme used to reduce high levels of plasma uric acid (UA) resulting from tumor lysis syndrome (TLS) in pediatric patients. Rasburicase reduces UA levels within 4 hours of administration, minimizing risk of serious complications from TLS. Although the efficacy of rasburicase has been demonstrated in clinical trials, there are few studies that have evaluated the economic implications of using rasburicase rather than allopurinol, the current standard of care. Methods: Pediatric patients administered rasburicase or allopurinol within 2 days of hospital admission were eligible for study inclusion. Patients were excluded if they were ≥ 18 years of age or received hemodialysis on admission. Patients receiving allopurinol or combination therapy were then propensity score matched to rasburicase patients based on gender, race, hospital type, provider type, payer type, admission source, use of electrolyte modification therapy, critical care admission, and comorbid diagnoses. Differences in healthcare costs, length of stay, and duration of subsequent critical care were assessed using gamma distributed generalized linear models with a log link function. Results: There were 63 allopurinol and 63 rasburicase patients matched in the analysis. The mean age of the sample was 7.4 years, with 27% being female. There were no statistical differences in matched covariates across the cohorts. Rasburicase patients incurred an average of $30,470 per hospitalization compared to $35,165 for allopurinol patients (p = 0.427). Mean length of stay was not statistically different across the cohorts, averaging 14 days. Duration of critical care was significantly lower for rasburicase (1.4 days) when compared to allopurinol (2.5 days, p = 0.0001). Conclusions: Treatment with rasburicase is associated with similar costs and a lower duration of critical care when compared to allopurinol therapy.

[Table: see text]
Randomized phase II trial of nanoparticle albumin-bound paclitaxel in three dosing schedules with bevacizumab as first-line therapy for HER2-negative metastatic breast cancer (MBC)
Authors: Conlin A. K. , Hudis C. A. , Bach A. , Moynahan M. , Lake D. , Forero-Torres A. , Wright G. , Hackney M. , Clawson A. , Seidman A. D.
Published: August 2020

1006

Background: Nanoparticle albumin-bound paclitaxel (nab-P) 260 mg/m2 is superior to paclitaxel 175 mg/m2 (P) every 3 weeks (Gradishar et al., J Clin Oncol. 2005). Weekly uninterrupted P is more effective than q3wk P in MBC (Seidman et al., J Clin Oncol. 2008). Bevacizumab (bev) nearly doubles response rate and time to progression (TTP) when added to P as 1st line therapy for MBC (Miller et al., N Engl J Med. 2007). Methods: This open-label, phase II study randomized patients (pts) to nab-P at 260 mg/m2 q3wk (arm A) versus 260 mg/m2 q2wk with filgrastim (arm B) versus 130 mg/m2 weekly uninterrupted, all with bev (15 mg/kg q3wk arm A, 10 mg/kg q2wk arms B and C). Pts were required to have measurable, HER-2-negative MBC and no prior chemotherapy for MBC. The primary endpoints were response rate and toxicity. Results: Accrual is complete, with 25% of pts still on study as of December 1, 2008. Of 208 pts randomized, 202 (72 arm A, 54 arm B, 76 arm C) were treated, with balanced demographics and baseline characteristics. The median age was 56 (range 29–85). 89% had visceral disease and 61% had prior neo-adjuvant or adjuvant chemotherapy. No significant differences in confirmed complete and partial response rates were noted (A: 42%, B: 42%, C: 41%). TTP was longer in arm C (9.2 months) versus both arms B (6.4 months) and A (7.7 months), overall p = 0.028. As per protocol-specified stopping rule, arm B was closed early due to unacceptable safety profile with significantly more grade ≥ 2 fatigue (B:57%, A: 39%, C:39%, p = 0.048) and bone pain (B: 19%, A: 10%, C:4%, p = 0.024). Neurotoxicity grade ≥ 2 was equivalent across all 3 arms (50%); febrile neutropenia occurred in <2% of pts in all arms. Arm C had significantly less arthralgia, myalgia, and nausea compared with arms A and B. Conclusions: Significant antitumor activity was observed in all arms. Weekly nab-P with bev (Arm C) resulted in a significantly longer TTP. Weekly nab-P with bev (Arm C) appears to have the highest therapeutic index, however sensory neuropathy is limiting, suggesting a 3 week on/1 week off schedule could be preferable and should be studied comparatively.

[Table: see text]
Treatment of childhood glial tumors with cisplatin and irinotecan
Authors: Mora J. , Cruz O. , Parareda A. , Guillen A. , Puy R. , Massaguer S. , de Torres C. , Garcia G. , Costa J. M.
Published: August 2020

10062

Background: Childhood glial tumors are heterogeneous neoplasias for which non-surgical management is controversial. After a pilot study suggesting that irinotecan/cisplatin (I/C) may be effective in children (Mora et al, Neuro Oncol 2007), we initiated a phase II prospective trial with the aim of avoiding radiation therapy for low grade's (LG) and improve outcome for high grade's (HG). Methods: The indication for adjuvant therapy was based upon histology, the extent of surgical resection, and the presence of clinical or neuroradiological signs of progression. Weekly Irinotecan (50 mg/m2 and 65 mg/m2 the last 2 cycles) and Cisplatin (30 mg/m2) for four consecutive weeks (1 cycle), and a total of 4 cycles was used. Results: From January 2004 to December 2007, 30 children aged 6 months to 17 years were treated, 21 at diagnosis, 7 at progression and 2 at relapse. Fourteen tumors were WHO grades I-II gliomas (LGG), 10 grade III (6 gliomas, 2 anaplastic ependymomas and 2 AT/RT), and 6 had no biopsy (3 brainstem (BST) and 3 optic-pathway tumors (OPT)). Two patients had type-1 neurofibromatosis and OPT. Primary sites included: 4 supratentorial, 8 BST, 9 OPT, 2 cerebellar, and 7 spinal. Prior to the I/C regimen, gross total resection was performed in 7 and biopsy in 14 tumors; 9 patients received chemotherapy and 5 radiotherapy. All but 6 patients, 2 because of C allergy and 4 BST because of progression, completed the protocol, with no grade 3–4 side effects. Vomiting was the main side effect. Twenty (90%) of 22 patients with evaluable clinical symptoms had a complete and rapid response, with objective functional recovery. With a median follow-up of 25 months, 14 (47%) patients had a complete/partial response (7 out of 10 HG), 10 (40%) had stable disease (8 out of 14 LG), and 6 (20%) progressed (all BST). Five patients died of disease, all BST. Twenty-five (83%) patients remain progression-free, median 27 months from protocol entry. Conclusions: Seventy percent objective response rate for HG and avoidance of radiotherapy for 93% of LG was obtained using the I/C regimen. Remarkable fast clinical responses and functional recoveries occurred.

No significant financial relationships to disclose.
Off-label drug use in women with breast cancer
Authors: Dean-Colomb W. , Fang S. , Smith W. , Michaud L. , Hortabagyi G. N. , Giordano S.
Published: August 2020

1016

Background: Despite reports of widespread use of off-label agents in cancer treatment, little is known about the off-label use of agents in the treatment of breast cancer patients. Methods: We used data from the Surveillance, Epidemiology, and End Results (SEER) - Medicare linked database to identify 2082 persons older than 65 years who were diagnosed with distant stage breast cancer between 1991 and 2002 and who were treated with chemotherapy between diagnosis and death. Off versus on-label classification was based upon FDA-approved indication in the treatment of breast cancer. We calculated the percentage of patients receiving off-label chemotherapy and used multivariate logistic regression models to estimate predictors of off-label chemotherapy use. We also evaluated the appropriateness of off-label chemotherapy drugs using DRUGDEX classifications. Results: Overall, 34.9% of patients were treated with off-label chemotherapy drugs. Of the thirty-six agents that were used to treat these patients, only 8 (22%) were FDA-approved for use in the treatment of breast cancer. Off-label use was least common in patients age 80 years and older (OR 1.93, 95% 1.35–2.76 for 80+ vs. 66–70 years) and varied by diagnosis year and geographic region. The most commonly used off-label agents were vinorelbine and gemcitabine, with 16.0% and 8.4% of patients receiving these agents, respectively. While 71% of the drugs used off-label lacked supporting evidence for their use in the treatment of breast cancer, these drugs were used in a small number of patients. Only 6.7% of patients were treated with drugs considered inappropriate for use in the treatment of breast cancer. Conclusions: Off-label chemotherapy use is widespread among patients with metastatic breast cancer. However, the majority of patients who received off-label chemotherapy received drugs with scientific data supporting such use.

No significant financial relationships to disclose.
Use of BIBW 2992, a novel irreversible EGFR/HER2 tyrosine kinase inhibitor (TKI), to treat patients with HER2-positive metastatic breast cancer after failure of treatment with trastuzumab
Authors: Hickish T. , Wheatley D. , Lin N. , Carey L. , Houston S. , Mendelson D. , Solca F. , Uttenreuther-Fischer M. , Jones H. , Winer E.
Published: August 2020

1023

Background: BIBW 2992 (Tovok) is an oral, novel, and potent, irreversible dual epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor-2 (HER2) inhibitor, with preclinical activity in trastuzumab-resistant cell lines overexpressing HER2 and phase I clinical activity. A phase II study of BIBW 2992 in patients with HER2-positive breast cancer who have failed treatment with trastuzumab is currently being conducted in the US and the UK. Methods: This is a multi-institutional open label single arm phase II study, planning to recruit 40 patients. Eligibility criteria include stage IIIB or IV HER2-positive metastatic breast cancer, progression following receipt of trastuzumab or intolerance of trastuzumab, measurable disease, Eastern Cooperative Oncology Group (ECOG) performance status of 0–2 and adequate organ function. Patients receive 50 mg BIBW 2992 once daily until disease progression. Tumor assessments are performed every two courses (one course = 28 days). The primary endpoint is objective response rate (RECIST criteria). Safety data are also collected. Results: To date, 40 patients have started treatment on the trial. Patients had received a median of three lines of prior therapy. Nine patients discontinued treatment prior to the first assessment at 8 weeks; four due to disease progression, four due to adverse events and one due to withdrawal of consent. Twenty-one patients have had tumor assessment after 8 weeks of treatment. Of these, four patients had a partial response (PR) and 10 patients had stable disease (SD). The PR has been confirmed at 16 weeks in one patient. The most frequently observed side effects to date are rash (Common Toxicity Criteria for Adverse Events [CTCAE] grade 3 in 4 patients) and diarrhea (CTCAE grade 3 in 8 patients). There were 20 dose reductions in 17 patients. Conclusions: BIBW 2992 at 50 mg/day induced responses and seems promising in HER2-positive breast cancer patients who have failed treatment with trastuzumab. Manageable cutaneous adverse events and diarrhea were the main side effects.

[Table: see text]
α-basic-crystallin expression in basal-like breast cancer and its association with brain metastasis
Authors: Kennecke H. F. , Voduc D. , Leung S. , Cryns V. L. , Perou C. M. , Nielsen T. O. , Cheang M.
Published: August 2020

1025

Background: Basal-like breast cancers are high grade tumors with poor prognosis, having propensity for brain and lung metastasis (Perou et al. Nature 406:747–52, 2000, Cheang et al. Clin Cancer Res 14:1368–76, 2008, Luck et al. Clin Oncol (R Coll Radiol) 20:40–5, 2008). α-basic-crystallin (αBC), a small heat shock protein with anti-apoptotic and oncogenic activity, is expressed in about half of basal-like breast cancers but only 6% of other types (Moyano et al. J Clin Invest 116:261–70, 2006). Here we investigate the association of αBC with sites of distant metastasis in a large cohort of breast cancer patients. Methods: Our cohort consists of 4046 early invasive breast cancers referred to the British Columbia Cancer Agency from 1986 to 1992. Archival paraffin tissue blocks were used to construct tissue microarrays. Breast cancer subtypes were defined using a surrogate of six immunohistochemical markers: ER, PR, HER2, Ki-67, epidermal growth factor receptor and cytokeratin 5/6. αBC immunostaining was scored by pre-established, published criteria. All documented sites of distant metastasis were abstracted by chart review according to predefined categories. The null hypothesis was tested using chi-square and Fisher's Exact tests; all tests were two-sided. Results: Among 3,248 cases with interpretable αBC data, 11% were αBC +. Among patients who developed distant metastatic disease, the 10-yr BCSS survival in αBC+ and - tumors was 12% and 29%. Sites of metastatic disease included: brain (15%), lung (35%), liver (35%) and bone (65%). Brain metastasis was significantly more common among αBC positive tumors (Fisher's Exact test p<10e-8). Basal-like tumors with brain metastasis commonly co-expressed αBC (Chi-square p=0.006). Conclusion: αBC is significantly associated with brain metastasis, particularly among basal breast cancers. These findings suggested that αBC may be involved in tumor cell metastasis and may allow early identification of a subset of patients at particularly high risk of brain metastasis.

[Table: see text]

No significant financial relationships to disclose.
Bevacizumab and pegylated liposomal doxorubicin as first-line therapy for locally recurrent or metastatic breast cancer: A multicenter, single-arm phase II trial of the Swiss Group for Clinical Cancer Research (SAKK)
Authors: Rochlitz C. , Spirig C. , Ruhstaller T. , Suter T. , Bühlmann M. , Fehr M. , Schönenberger A. , Lerch S. , Mayer M. , Zaman K.
Published: August 2020

1030

Background: Bevacizumab in combination with taxanes has become a standard first-line treatment of advanced breast cancer in some countries, but there is no information on its use in combination with pegylated lipsomal doxorubicin in metastatic breast cancer. Therefore, we performed a multicenter, single-arm phase II trial to evaluate the toxicity and efficacy of pegylated liposomal doxorubicin (PLD) and bevacizumab (B) as first-line treatment in advanced breast cancer. Methods: PLD at a dose of 20 mg/m2 and B at 10 mg/kg were infused on days 1 and 15 of each 4-week cycle for a maximum of 6 cycles. Thereafter, B monotherapy was continued at the same dose until progression or toxicity. Primary endpoint was the occurrence of specific toxic events known to strongly interfere with quality of life, i.e., severe cardiac toxicity, any grade 4/5 toxicity, and selected grade 3 nonhematological toxicities (hand-foot-syndrome, cognitive disturbance, CNS hemorrhage, and mucositis/stomatitis). Secondary endpoints included overall response, progression free survival (PFS), time to treatment failure, and duration of response. Eligibility criteria included documentation of metastatic or inoperable breast cancer; measurable disease according to RECIST; erbB2-negativity; LVEF of ≥ 55%; WHO performance status 0 or 1. The study used a Herndon's two-stage design with 14 and 29 patients for stages 1 and 2, respectively. The promising rate of primary toxicity was <15% and the uninteresting rate >33%. The type I error probability was 5% and the power 80%. Results: The trial had to be stopped prematurely because of toxicity after the enrollment of 41 evaluable patients. Among these patients, 16 (39%) had grade 3 hand-foot syndrome, 1 grade 3 mucositis and 1 grade 4 cardiac toxicity. Thus, a total of 18/41 (44%, exact 95% c.i. 28–60%) of all patients had a primary toxicity. Best overall response rate was 23.3% (exact 95% c.i. 12–39%), median PFS was 7.5 months (95% c.i. 4.6–8.1 months). Conclusions: The combination of 2-weekly PLD and B in advanced breast cancer is surprisingly toxic and only modestly active and should not be further investigated.

[Table: see text]
Safety and efficacy of first-line bevacizumab (B) plus chemotherapy (CT) for locally recurrent or metastatic breast cancer (LR/mBC): Analysis of MO19391 according to CT
Authors: Pierga J. , Pritchard K. I. , Thomssen C. , Cortes-Funes H. , Biganzoli L. , Padrik P. , Zvirbule Z. , Smith I.
Published: August 2020

1033

Background: Combination of B with first-line paclitaxel (TP) or docetaxel (TD) significantly improves PFS vs taxane alone in pts with LR/mBC. The open-label, multicenter MO19391 trial further assessed safety and efficacy of first-line B plus a taxane in >2,000 pts in routine clinical practice. Methods: Eligible pts had HER2- negative LR/mBC (or HER2-positive LR/mBC progressing after trastuzumab-containing therapy), ECOG PS 0–2, no prior CT for LR/mBC and no evidence of CNS metastases. Pts received B 10mg/kg q2w or 15mg/kg q3w plus the physician's choice of taxane (TP or TD alone or with another CT) or other non-anthracycline CT according to physician's standard of care. Treatment was continued until disease progression, unacceptable toxicity, or refusal. The primary endpoint was safety (NCI CTCAE v3.0); secondary endpoints included TTP, OS, and safety in pts developing CNS metastases. Results: From Sept 2006 to June 2008, 2,027 pts from 37 countries were enrolled. Median follow-up is 7.4 months. CT included a taxane (alone or with CT) in ∼75% of pts. Non-taxane agents included capecitabine (X) and vinorelbine (V). In the overall population, median age was 54 years (range 21–93), 70% were ER and/or PgR positive, and 32% had disease-free interval (DFI) ≤24 months. Baseline characteristics were broadly similar across subgroups. However, the X monotherapy subgroup included fewer pts with >3 metastatic lesions and more with a DFI ≤24 months and/or triple-negative disease compared with other subgroups. Safety and efficacy results grouped by CT are shown below. OS data are still immature (85% of pts alive at this analysis). Conclusions: In this large phase IV study, safety and efficacy of B plus TP or TD was similar to results of E2100 and AVADO. Variations in toxicities were consistent with the known profiles of each CT and no new safety signals for B were observed. The lowest incidences of serious Aes were seen with B plus TP or X. TTP was shorter with X and non-taxane combinations. Such findings are potentially attributable to small pt numbers and differences in baseline characteristics. These results show that B can be safely and effectively combined with a wide range of commonly used CT regimens as first-line therapy for mBC.

[Table: see text]

[Table: see text]
Outcomes of first-line chemotherapy for advanced breast cancer in women with good versus poor quality of life at baseline
Authors: Lee C. , Stockler M. , Gebski V. , Coates A. , Simes R. J.
Published: August 2020

1036

Background: Health-related quality of life (QL) is an established predictor of outcome in advanced breast cancer. The benefits and harms of chemotherapy in women with poor QL are unclear. Methods: We used data from 378 women receiving classical CMF in the control arms of 3 randomized trials. QL was rated at baseline by patients with linear analogue self-assessment scales (LASA) for physical well-being (PWB), mood, appetite, pain, nausea/vomiting, and overall QL; and by physicians with Spitzer's Quality-Of-Life Index (QL-I). Patients were divided into 3 groups according to their baseline QL scores: good (LASA 0–25, QL-I 5–7), intermediate (LASA 26–65, QL-I 8–10) or poor (LASA 66–100, QL-I 11–15). The main outcomes were overall survival (OS), progression-free survival (PFS), objective tumor response (OTR = CR or PR), weight loss, and grade 3 or 4 adverse events (AE). Results: All aspects of QL, except nausea/vomiting, were significant univariable predictors of OS and PFS. PWB, mood, appetite and QL-I were independently significant predictors of OS in a multivariable model with biomedical factors. Only patient's self-rated poor QL had lower rates of OTR, and higher rates of nonhematological AE than those with good QL (see Table), but rates of hematological AE were similar. Weight loss occurred more frequently in those with poor appetite (OR 5.8, p=0.05) or poor PWB (OR 4.9, p=0.05). Conclusions: Less than 25% of women with poor baseline QL responded to first line CMF but over 25% had severe non-hematological toxicity. Baseline QL predicts these outcomes beyond biomedical factors.

[Table: see text]

No significant financial relationships to disclose.
The association of metabolic syndrome with triple-negative breast cancer
Authors: Maiti B. , Kundranda M. N. , Jin T. , Spiro T. P. , Daw H. A.
Published: August 2020

1038

Background: Metabolic syndrome, a conglomerate of obesity, insulin resistance, hypertriglyceridemia, low HDL (high density lipoprotein), and hypertension is associated with an increased risk of breast cancer. However, no clear association has been shown between the highly aggressive triple-negative breast cancer and metabolic syndrome. Methods: In a retrospective review we compared triple-negative and non-triple-negative breast cancer cases for the presence of metabolic syndrome by NCEP (National Cholesterol Education Program) or AACE (American Association of Clinical Endocrinologists) definitions. Data on metabolic syndrome criteria, tumor size, grade, lymph node status, and ductal carcinoma in situ (DCIS) were reviewed. Chi-square test or Student's t-test was used for data analysis. Results: The entire cohort of 176 patients (12.5% African-American) with median age 56.5 years (range 26–91 years) comprised of 86 triple-negative cases and 90 non-triple-negative cases. A statistically significant association of triple-negative breast cancer with metabolic syndrome was observed. According to the NCEP criteria 58.1% of triple negative patients had metabolic syndrome as compared to only 36.7% of non-triple negative patients (p = 0.004). Consistently, by the AACE criteria 52.3% of triple negative patients had metabolic syndrome as compared to 34.4% of non-triple negative patients (p = 0.017). Contrary to blood glucose, triglyceride, or HDL levels, which independently showed significant association with triple-negative breast cancer, hypertension, or BMI showed no independent association. Additionally, triple-negative tumors displayed a significantly higher histologic grade and relative paucity of ductal carcinoma in situ (DCIS) when compared to the non-triple negative tumors (p < 0.001). Conclusions: The data suggests that the metabolic syndrome is significantly more prevalent in triple-negative breast cancer patients when compared to the non-triple-negative patients. Additionally, triple-negative breast cancer showed a significantly higher histologic grade and a relative absence of DCIS. Whether the presence of metabolic syndrome preferentially increases the risk of developing triple-negative-breast cancer needs to be elucidated by future prospective studies.

No significant financial relationships to disclose.
Clinical benefit of lapatinib-based therapy in patients with HER2-positive breast tumors expressing p95HER2
Authors: Prudkin L. , Aura C. M. , Jimenez J. , Scaltriti M. , Ellis C. , Gagnon R. , Arbushites M. , Liu Y. , Koehler M. , Baselga J.
Published: August 2020

1048

Background: Approximately 25% of HER2 overexpressing breast tumors express a truncated form of the receptor (p95HER2) that lacks the extracellular domain but retains kinase activity. p95HER2-positive tumors are associated with a worse prognosis and resistant to trastuzumab therapy. In preclinical models, lapatinib (L), a tyrosine kinase inhibitor of EGFR and HER2, is active in p95HER2 expressing tumors. The aim of this analysis was to test the hypothesis that benefit from L-based therapy is independent of p95HER2 expression in 2 clinical trials in patients (pts) with HER2-positive tumors treated with either L monotherapy (Study EGF20009 ) or L in combination with capecitabine (Study EGF100151). Methods: Pre-treatment tumor tissue from both trials (N=201) was analyzed for p95HER2 expression by immunofluorescence as previously described (Scaltriti M. et al, JNCI 2007). Expression of p95HER2 was correlated with clinical benefit rate (CBR: complete response [CR] + partial response [PR] + stable disease [SD] ≥ 24 weeks) and progression-free survival (PFS) using logistic regression and Cox-proportional hazard models. Results: 68/105 and an initial 72/96 tissue samples were evaluable for p95HER2 expression from studies EGF20009 and EGF100151, respectively. The Table summarizes the results from the L treated pts. The CBR and PFS in L treated pts were not significantly different between the p95HER2 subgroups. Expanded data for p95HER2 expression in additional EGF100151 tumor samples will be presented. Conclusions: L as a monotherapy or in combination with capecitabine has similar response activity in pts with p95HER2-positive and p95HER2-negative HER2-positive breast tumors.

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First-line treatment with lapatinib plus paclitaxel versus paclitaxel alone for patients with HER2+ metastatic breast cancer (MBC): Quality-of-life (QOL) analysis using repeated measures and pattern mixture models
Authors: Sherrill B. , Wu Y. , Amonkar M. , Arbushites M. , DiLeo A.
Published: August 2020

1049

Background: A phase III randomized, multicenter, double-blind, placebo-controlled study compared first-line therapy with lapatinib and paclitaxel (L+P) versus paclitaxel alone (P) for MBC. In a sub-group analysis of HER2+ patients, time to tumor progression for L+P was significantly improved, with an emerging trend for survival benefit. This analysis models the QOL data in the subset of the randomized ITT population that overexpressed HER2 (FISH+ or IHC3+). Methods: QOL was assessed using the Functional Assessment of Cancer Therapy-Breast (FACT-B) questionnaire. Outcome measures included FACT-B total score, trial outcome index (TOI) score and breast cancer subscale (BCS). Higher scores represent better QOL. Patients completed the FACT-B at the screening visit, week 9, every 12 weeks thereafter, and at discontinuation of therapy. The assessment at discontinuation was applied to the next scheduled visit for analyses. Changes from baseline were analyzed using repeated measures models with baseline score as a covariate. Pattern mixture modeling was implemented as a sensitivity analysis. Results: Of 579 randomized patients, 86 were HER-2+ and 85 completed at least one item from the FACT-B (n = 48 L+P; n = 37 P). The baseline characteristics of this subset were well-matched with regard to age, ECOG status, and prior anthracycline use. More patients in the L+P group than in the P group had visceral disease (69% vs 51%) and more were at stage IV (88% vs 78%).Over the first year, the L+P arm demonstrated stable FACT-B scores over time, whereas average scores for patients on paclitaxel monotherapy decreased (change from baseline: L+P p = 0.99; P p = 0.01). Statistically significant differences were observed between treatment arms on the FACT-B (p = 0.05), TOI (p = 0.03), and BCS (p = 0.01). Pattern mixture models suggested more QOL differentiation between treatments among patients who progressed or withdrew within 6 months of study start. Conclusions: Among patients with HER2+ MBC, treatment with L+P resulted in more stable QOL than with P monotherapy. These findings represent clinically important differences between treatment groups.

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Evaluation of the presence of IGF1R overexpression in wild-type and kinase mutant GI stromal tumors
Authors: Corless C. L. , Beadling C. , Justusson E. , Heinrich M. C.
Published: August 2020

10506

Background: Most adult GI stromal tumors have gain-of-function mutations in KIT (80%) or PDGFRA (5–7%). These pathogenetic mutations are the target for kinase inhibitor therapy. The pathogenesis of the 10–15% of GISTs lacking kinase mutations (WT GIST) is unknown; this includes most pediatric GISTs. Recently, Tarn et al. (PNAS 2008) identified IGF1R over-expression in all WT GIST in their series of cases, including one pediatric case. IGF1R may represent a novel therapeutic target for WT GISTs. Methods: We developed a quantitative RQ-PCR assay for IGF1R and GAPDH transcripts that is linear over 5 logs (R2 values of 0.99 and 0.98, respectively). We prepared cDNA from RNA isolated from 79 archival, formalin-fixed, paraffin-embedded GIST specimens and quantified IGF1R expression as the % ratio of IGF1R/GAPDH transcripts. We had previously genotyped the tumors to identify any kinase mutations. Results: Adult WT GIST had a 10–15 fold higher expression of IGF1R transcript than kinase mutant GISTs (WT GIST 13.7 ±18, n=35; KIT exon 11 mutant GIST 1.0 ± 1.1, n=26; PDGFRA mutant GIST 0.9 ± 1.0, n=8; KIT 9 or 13 mutation 0.8 ± 0.6, n=5). Interestingly, the WT GIST group could be further divided into tumors with low vs. high IGF1R expression. The low IGF1R expression group (mean 0.6, range 0.1–1.9, n=14), had similar IGF1R expression to kinase mutant GISTs. In contrast, the high expression group had more than 30-fold higher levels of IGF1R transcript (mean 22.5, range 7.3–76.5, n=21). We also examined IGF1R expression in 5 WT pediatric GISTs. The mean IGF1R expression in pediatric GISTs resembled that of the adult high expression group, with 4 of 5 cases showing IGF1R over-expression. Conclusions: WT GISTs are heterogeneous with regard to IGF1R expression and can be divided into two subgroups. One third of the WT GISTs overlap with kinase-mutant GISTs, while the remainder express IGF1R at more than 30-fold higher levels. These results have implications for evolving models of GIST pathogenesis and the clinical testing of IGF1R monoclonal antibodies for treatment of metastatic GIST.

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Masatinib mesylate in imatinib-naive locally advanced or metastatic gastrointestinal stromal tumor (GIST): Results of the French Sarcoma Group phase II trial
Authors: Le Cesne A. , Blay J. , Bui N. B. , Bouché O. , Adenis A. , Domont J. , Cioffi A. , Moussy A. , Hermine O.
Published: August 2020

10507

Background: Masitinib mesylate (AB1010, AB Science, Paris, France) is a novel protein tyrosine kinase inhibitor which, in vitro, has greater activity and selectivity than imatinib mesylate against bith wild-type c-Kit receptor and its mutated form in the juxtamembrane region. Masatinib also inhibits PDGFR and FGFR3. This multicenter phase II study evaluated the efficacy and safety of masatinib as a first-line treatment of advanced GIST. Methods: Imatinib-naïve patients with inoperable, locally advanced or metastatic GIST received oral masatinib (7.5 mg/kg/day) until progression, refusal or toxicity. A Simon “minimax two stage” design was used. Efficacy variables included response rate at two months, best response according to RECIST, disease control rate (DCR), metabolic response rate and progression free survival (PFS). Results: 30 patients with a median age of 58 years (60% of males) were included from June 2005 to April 2007 in five French institutions. The most frequent relevant grade 3 toxicities were rash (10%), neutropenia (7%) and abdominal pain (7%). One patient presented a grade 4 skin exfoliation. Three patients discontinued treatment due to suspected toxicity. At two months, the response rate was 20% (6/30 patients) according to RECIST (DCR of 98.7%, 29/30 patients) and 84.6% (11/13 evaluable patients) according to FDG-PET response criteria. After a median follow-up of 23.7 months, there were 6.7% of CR, 43.3% of PR, 46.7% of SD and 3.3% of PD as best response (DCR of 96.7%). Mean time to response was 5.7 months (0.8 to 23.3 months). The median PFS was 27.2 months with PFS rates of 68.8% at 1 year and 60.2% at 2 years. Up to date, all but one patient are alive (one patient died of post-surgical complications, unrelated to treatment). Mutational analyses of the patients’tumors are ongoing. Conclusions: The results observed with masatinib compare favorably with those reported with imatinib in front-line treatment of advanced GIST both in term of safety and efficacy and support the initiation of a phase III randomized clinical trial.

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GEP01: A phase I study of lapatinib (L) and vinorelbine (VNR) in HER2 overexpressing (HER2+) locally advanced or metastatic breast cancer (LAMBC) patients (pts): A FNCLCC Group of early phase trials study
Authors: Brain E. , Dalenc F. , Lokiec F. , Dieras V. , Bonneterre J. , Rezaï K. , Mefti-Lacheraf F. , Roché H. , Jimenez M. , Fumoleau P.
Published: August 2020

1051

Background: Lapatinib is an effective anti-HER-2 therapy in LAMBC pts, currently investigated in the adjuvant setting. Following anthracyclines, taxanes and capecitabine, VNR is an active agent in metastatic setting. Its main toxicity consists of neutropenia and may challenge the standard weekly, day D1 and D8 regimen. We investigated the combination of L + VNR, seeking the recommended dose for further phase II studies and the potential pharmacokinetic (PK) interactions. Methods: Women with a HER-2+ LAMBC, in progression after ≤ 2 lines of trastuzumab-based treatment were treated with a 7D (D-7 to D0) loading dose of L before starting VNR on a D1 and D8 q3w IV regimen. L was given orally continuously. Primary prophylaxis of febrile neutropenia (FN) with G-CSF was not permitted. Dose levels (DL, L [mg]/VNR [mg/m2]) ranged from 750/20 to 1250/30 with 3 pts/DL (6 in case of dose-limiting toxicity [DLT]). DLT was defined on tolerance at cycle 1 and included grade (gr) 4 neutropenia (PN) ≥ 7D, FN, thrombocytopenia (gr4 or symptomatic gr3), omission of D8 for haematological toxicity, and any drug-related gr3–4 non-haematological toxicity. PK samples were collected on 7 points on D1 of cycle 1 for L and VNR dosages. Results: From August 2007 to December 2008, 15 evaluable pts were enrolled (median age 58 [46–75], 43% PS 0, 8 pts previously exposed to only 1 line of trastuzumab) and 65 cycles were administered. Toxicity is available for 13 pts. Of 3 pts treated at DL4 (1000/25), 2 developed a DLT: 1 FN and 1 gr4 PN > 7D. Other significant toxicities (% pts) included gr2 anaemia 8%, gr4 PN 46%, gr1 diarrhoea 62%, gr2 nausea/vomiting 8%, gr1 skin rash 23%, gr2 transaminases 23%; no decrease of cardiac function occurred. From DL1 to DL3 (750/20, 1000/22.5), total body clearance of VNR decreased by 50% (32 ± 19 L/h vs 17 ± 7 L/h). Conclusions: Maximal tolerated dose has been reached at 1000/22.5 for the combination of L with VNR given on a D1 and D8 q3w schedule. Given a potential PK interference which would yield to higher exposure to VNR, an intermediate DL is going to be explored (1250/22.5) to allow an accurate definition of the recommanded dose of the combination for future phase II comparison studies.

[Table: see text]