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Blockade of insulin-like growth factors increases efficacy of paclitaxel in metastatic breast cancer.

ABSTRACT: Breast cancer remains the leading cause of cancer death in women owing to metastasis and the development of resistance to established therapies. Macrophages are the most abundant immune cells in the breast tumor microenvironment and can both inhibit and support cancer progression. Thus, gaining a better understanding of how macrophages support cancer could lead to the development of more effective therapies. In this study, we find that breast cancer-associated macrophages express high levels of insulin-like growth factors 1 and 2 (IGFs) and are the main source of IGFs within both primary and metastatic tumors. In total, 75% of breast cancer patients show activation of insulin/IGF-1 receptor signaling and this correlates with increased macrophage infiltration and advanced tumor stage. In patients with invasive breast cancer, activation of Insulin/IGF-1 receptors increased to 87%. Blocking IGF in combination with paclitaxel, a chemotherapeutic agent commonly used to treat breast cancer, showed a significant reduction in tumor cell proliferation and lung metastasis in pre-clinical breast cancer models compared to paclitaxel monotherapy. Our findings provide the rationale for further developing the combination of paclitaxel with IGF blockers for the treatment of invasive breast cancer, and Insulin/IGF1R activation and IGF+ stroma cells as potential biomarker candidates for further evaluation.

SUBMITTER: Ireland L

PROVIDER: S-EPMC5895608 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Blockade of insulin-like growth factors increases efficacy of paclitaxel in metastatic breast cancer.

Ireland Lucy L Santos Almudena A Campbell Fiona F Figueiredo Carlos C Hammond Dean D Ellies Lesley G LG Weyer-Czernilofsky Ulrike U Bogenrieder Thomas T Schmid Michael M Mielgo Ainhoa A

Oncogene 20180125 15

Breast cancer remains the leading cause of cancer death in women owing to metastasis and the development of resistance to established therapies. Macrophages are the most abundant immune cells in the breast tumor microenvironment and can both inhibit and support cancer progression. Thus, gaining a better understanding of how macrophages support cancer could lead to the development of more effective therapies. In this study, we find that breast cancer-associated macrophages express high levels of ...[more]

PMID: 29367764

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Project description:Our study aimed to compare the efficacy and safety of nab-paclitaxel plus cisplatin (AP) with nab-paclitaxel plus gemcitabine (AG) in patients with metastatic breast cancer (MBC). We collected data from two single-arm, phase II MBC studies. In NCT01149798, seventy-three MBC patients received 125 mg/m2 nab-paclitaxel on days 1, 8 and 15 followed by 75 mg/m2 cisplatin on day 1 of a 28-day cycle. In NCT01550848, eighty-four MBC patients received 125 mg/m2 nab-paclitaxel and 800 mg/m2 gemcitabine on days 1, 8, and 15 of a 28-day cycle. The endpoints were the overall response rate (ORR), progression-free survival (PFS), overall survival (OS) and safety profiles of these regimens. Among the 157 patients included, the ORR were 67.1% and 52.4% for the AP and AG arms, respectively (odds ratio [OR] = 0.246; hazard ratio [HR] = 1.485; 95% confidence interval [CI], 0.762-2.985). After median follow-up periods of 26.3 and 23.3 months in the AP and AG arms, the median PFS were 9.8 months (95%CI, 8.1-11.6) and 8.1 months (95%CI, 6.8-9.4), respectively, while the median OS were 26.9 months (95%CI, 22.4-31.4) and 25.5 months (95%CI, 19.3-31.4), respectively. Neither PFS nor OS adjusted for the number of metastases, occurrence of liver metastasis and chemotherapeutic lines differed significantly between the two arms (PFS:HR = 0.769; 95%CI, 0.541-1.092; p = 0.142; OS:HR = 0.686; 95%CI, 0.426-1.104; p = 0.120). However, PFS was significantly better with AP than with AG in metastatic triple-negative breast cancer (mTNBC) patients (HR = 0.308; 95%CI, 0.129-0.732; p = 0.008). Adverse events were more common with AP than with AG, except for edema and myalgia. Both regimens showed substantial efficacy and were tolerated well in MBC patients. mTNBC who received AP rather than AG showed longer PFS. However, adverse events were more common with AP. Thus, AP may be worth recommending to mTNBC, while AG may be a better alternative for MBC patients with other subtypes.

Project description:Capecitabine and paclitaxel are established effective treatments, alone and combined with other cytotoxic and targeted agents, for metastatic breast cancer (MBC). Paclitaxel polyglumex (a macromolecular conjugate of paclitaxel bound to poly-L-glutamic acid) has potential advantages over conventional paclitaxel, including little alopecia, short infusion time with no premedication, enhanced tumor permeability/retention effect, and improved tolerability. We therefore examined tolerability and efficacy of paclitaxel polyglumex with capecitabine in patients with MBC.This was a single-stage phase 2 study, with interim analysis conducted with endpoints of tumor response, adverse events (toxicities), time to progression, and overall survival. The main eligibility criteria were: age >18 years, no prior MBC chemotherapy, Eastern Cooperative Oncology Group performance score <2, disease measurable by RECIST criteria, no HER2 overexpression or amplification, no brain metastases or peripheral sensory neuropathy. Treatment consisted of paclitaxel polyglumex (135 mg/m) by intravenous infusion on day 1+capecitabine (825 mg/m) orally twice daily on days 1 to 14, repeated on a 3-week cycle. Forty-one evaluable patients were required to test the null hypothesis that the complete and partial tumor response rate (CR+PR) was at the most 40% against the alternative of at least 60%. Paclitaxel polyglumex+capecitabine would be considered promising in this population if ?21 responses were observed among first 41 evaluable patients.Forty-eight patients were enrolled between April 2006 and April 2007; all patients were evaluable. The median number of treatment cycles administered was 6. Eighteen patients [38%; 95% confidence interval (CI), 24%-53%] had a confirmed tumor response (2 CR, 16 PR) by RECIST criteria. Fifteen (38%; 95% CI, 23%-53%) responses occurred in first 41 patients, falling short of prespecified goal of 21 responses. Median duration of tumor response was 13.2 months. Three of the responders were progression free at last follow-up with a median follow-up of 43 months. Median progression-free survival was 5.1 months (95% CI, 4.0-7.6 mo). Six-month progression-free survival was 42% (95% CI, 30%-58%). Median dose level administered was paclitaxel polyglumex (135 mg/m) and capecitabine (825 mg/m) for cycles 1 to 7. Most common severe (grade 3/4) toxicities (at least possibly related to study drug) were: leukopenia 9 (19%), neutropenia 8 (17%), neurosensory 4 (8%), skin reaction-hand/foot 4 (8%), and dyspnea 2 (4%). Forty-six percent (22/47) of patients experienced grade ?3 toxicity and 8% (4/48) experienced grade ?4 toxicity. No alopecia was reported.Although the trial failed to reach goal of 21 confirmed tumor responses among the first 41 evaluable patients, paclitaxel polyglumex and capecitabine is well tolerated and effective in MBC.

Project description:ImportanceElevated expression of AURKA adversely affects prognosis in estrogen receptor (ER)-positive and ERBB2 (formerly HER2)-negative and triple-negative breast cancer and is associated with resistance to taxanes.ObjectiveTo compare paclitaxel alone vs paclitaxel plus alisertib in patients with ER-positive and ERBB2-negative or triple-negative metastatic breast cancer (MBC).Design, setting, and participantsIn this randomized clinical trial conducted with the US Oncology Network, participants were randomized to intravenous (IV) paclitaxel 90 mg/m2 on days 1, 8, and 15 on a 28-day cycle or IV paclitaxel 60 mg/m2 on days 1, 8, and 15 plus oral alisertib 40 mg twice daily on days 1 to 3, 8 to 10, and 15 to 17 on a 28-day cycle. Stratification was by prior neo or adjuvant taxane and by line of metastatic therapy. Eligible patients were those who had undergone endocrine therapy, 0 or 1 prior chemotherapy regimens for MBC, more than 12 months treatment-free interval from neo or adjuvant taxane therapy, and with measurable or evaluable lytic bone-disease. Data were analyzed from March 2019 through May 2019.Main outcomes and measuresThe main outcome was progression-free survival (PFS) with secondary end points of overall survival (OS), overall response rate, clinical benefit rate, safety, and analysis of archival breast cancer tissues for molecular markers associated with benefit from alisertib.ResultsA total of 174 patients were randomized, including with 86 randomized to paclitaxel and 88 patients randomized to paclitaxel plus alisertib, and 169 patients received study treatment. The final cohort included 139 patients with a median (interquartile range [IQR]) age of 62 (27-84) years with ER-positive and ERBB2-negative MBC, with 70 randomized to paclitaxel and 69 randomized to paclitaxel plus alisertib. The TNBC cohort closed with only 35 patients enrolled due to slow accrual and were not included in efficacy analyses. The median (IQR) follow-up was 22 (10.6-25.1) months, and median (IQR) PFS was 10.2 (3.8-15.7) months with paclitaxel plus alisertib vs 7.1 (3.8-10.6) months with paclitaxel alone (HR, 0.56; 95% CI, 0.37-0.84; P = .005). Median (IQR) OS was 26.3 (12.4-37.2) months for patients who received paclitaxel plus alisertib vs 25.1 (11.0-31.4) months for paclitaxel alone (HR, 0.89; 95% CI, 0.58-1.38; P = .61). Grade 3 or 4 adverse events occurred in 56 patients (84.8%) receiving paclitaxel plus alisertib vs 34 patients (48.6%) receiving paclitaxel alone. The main grade 3 or 4 adverse events with paclitaxel plus alisertib vs paclitaxel alone were neutropenia (50 patients [59.5%] vs 14 patients [16.4%]), anemia (8 patients [9.5%] vs 1 patient [1.2%]), diarrhea (9 patients [10.7%] vs 0 patients), and stomatitis or oral mucositis (13 patients [15.5%] vs 0 patients). One patient receiving paclitaxel plus alisertib died of sepsis.Conclusions and relevanceThis randomized clinical trial found that the addition of oral alisertib to a reduced dose of weekly paclitaxel significantly improved PFS compared with paclitaxel alone, and toxic effects with paclitaxel plus alisertib were manageable with alisertib dose reduction. These data support further evaluation of alisertib in patients with ER-positive, ERBB2-negative MBC.Trial registrationClinicalTrials.gov Identifier: NCT02187991.

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Blockade of insulin-like growth factors increases efficacy of paclitaxel in metastatic breast cancer.

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Blockade of insulin-like growth factors increases efficacy of paclitaxel in metastatic breast cancer.

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