Bevacizumab In Breast Cancer Patients Research Articles

23P - Design of a protein signature predicting response to neo-adjuvant treatment with chemotherapy combined with bevacizumab in breast cancer patients

23P - Design of a protein signature predicting response to neo-adjuvant treatment with chemotherapy combined with bevacizumab in breast cancer patients

Pharmacogenetics revisits bevacizumab in breast cancer patients: An ancillary analysis of the UCBG trial COMET—A French multicentric prospective study from R&D UNICANCER.

1079 Background: Bevacizumab (Beva) is no longer unanimously recommended in the management of breast cancer (BC). Given the absence of faithful predictors of Beva treatment outcome, we made the hypothesis that constitutional gene polymorphisms could play a role in this context. We report the pharmacogenetic ancillary study of the prospective COMET trial conducted in advanced BC patients (pts) receiving first-line Beva associated with paclitaxel. Methods: Relevant targeted gene polymorphisms were analyzed (blood) in 203 prospective pts (mean age 55.3, median follow-up 24 months). VEGFA at positions -2578C > A (rs699947), -1498T > C (rs833061), -634G > C (rs2010963), and 936C > T (rs3025039) were analyzed by PCR-RFLP. VEGFR1 319A > C (rs9582036), VEGFR2 at positions 604C > T (rs2071559), 1192C > T (rs2305948), 1416T > A (rs1870377), IL8 251T > A (rs4073), CYP2C8 139C > T (rs1572080), 399T > C (rs10509681) and ABCB1 at positions 1199 C > TA (rs2229109), 2677G > TAC (rs2032582) were analyzed by Mass-Array Agena. ABCB1 1236C > T (rs1128503) and 3435T > C (rs1045642) were analyzed by pyrosequencing. All fitted HWE. Results: Median progression-free survival (PFS) was 10.8 months. VEGFR1 319A allele was associated with longer PFS (p = 0.03). The VEGFA-1498T allele was significantly associated with both longer overall survival (OS) (p = 0.005) and PFS (p = 0.065). The VEGFA -2578C allele was associated with greater OS (p = 0.002) and PFS (p = 0.071). These two VEGFA polymorphisms were in linkage disequilibrium (p < 0.0001). Multivariate Cox analysis showed that VEGFA -2578 (p = 0.001) and VEGFR2 1416 (p = 0.025) were significant predictors of OS: the score of favorable alleles (VEGFA -2575C and VEGFR2 1416T) was highly associated with OS (p = 0.0003), with median survival at 24 months being 30% for score 0 (95%CI 15-61), 65% for score 1 (95%CI 55-75) and 90% for score 2 (95%CI 67-90). Conclusions: Application of an easy-to-perform low-cost genotyping test may identify strong predictors of Beva outcome in metastatic BC pts. In the current era of precision medicine, a pharmacogenetic-based personalized Beva therapy deserves to be prospectively validated in BC pts. Clinical trial information: 2012-A00244-39.

Germline Genetic Variants in TEK, ANGPT1, ANGPT2, MMP9, FGF2 and VEGFA Are Associated with Pathologic Complete Response to Bevacizumab in Breast Cancer Patients.

BackgroundWe previously reported improved pathologic complete response (pCR) in a prospective phase II study using neoadjuvant bevacizumab in combination with chemotherapy compared to chemotherapy alone in breast cancer patients (41% vs. 25%, p = 0.0291). In this study, we queried germline single-nucleotide polymorphisms (SNPs) in angiogenesis-related genes for their impact on pCR and overall survival (OS).MethodsDNA for genotyping was available from 34 subjects who received bevacizumab in addition to chemotherapy and 29 subjects who did not. Using Illumina® technology, we queried 504 SNPs with a minor allele frequency (MAF) of at least 5%, located in 10 angiogenesis-related genes, for their effect on pCR via logistic regression with an additive-inheritance model while adjusting for race and bevacizumab treatment. SNPs that showed significant associations with pCR were selected for additional characterization.ResultsAfter adjusting for race and tumor type, patients who had bevacizumab added to their neoadjuvant therapy were found to experience a significantly improved rate of pCR compared to patients who did not (adjusted OR 8.40, 95% CI 1.90–37.1). When patients were analyzed for SNP effects via logistic regression with race and bevacizumab treatment included as covariates, two SNPs in angiopoietin 1 (ANGPT1), six in ANGPT2, three in fibroblast growth factor 2 (FGF2), four in matrix metalloproteinase 9 (MMP9), three in tyrosine kinase, endothelial (TEK) and two in vascular endothelial growth factor A (VEGFA) were associated with pCR (P<0.05). However, when overall survival was considered, there was no difference between treatment groups or between genotypes.ConclusionGenetic variability in TEK, ANGPT1, ANGPT2, FGF2, MMP9 and VEGFA is associated with pCR in bevacizumab-treated patients. Consistent with other studies, adding bevacizumab to standard chemotherapy did not impact OS, likely due to other factors and thus, while SNPs in TEK, ANGPT1, ANGPT2, FGF2, MMP9 and VEGFA were associated with pCR, they were not predictive of OS in this patient population.Trial RegistrationClinicalTrials.gov NCT00203502

Tolérance rénovasculaire du bévacizumab dans le cancer du sein. Valeur pronostique de l’hypertension et de la protéinurie

The potential prognostic value of hypertension and proteinuria of anti-vascular endothelial growth factor (VEGF) drugs has not been assessed in routine clinical practice so far in breast cancer. The objectives of the MARS study were to assess the prevalence of proteinuria and hypertension at baseline, their incidence under anti-VEGF treatment, and to evaluate a possible link with overall survival. Patients from 8 centres were included between 2009 and 2011 with a follow-up of 1 year. They were naive of any previous anti-VEGF treatment and planned to be started on one. The results of the group of patients with breast cancer receiving bevacizumab are presented. Four hundred and two patients with breast cancer and treated with bevacizumab were included. At inclusion, hypertension prevalence was 12.4%, proteinuria 23.9%. The incidence of de novo proteinuria and hypertension during the follow-up was 61.7% and 16.8%, respectively. Among patients with de novo proteinuria, 62.2% afterwards improved/normalized. No thrombotic microangiopathy was reported. Baseline or de novo proteinuria/hypertension were not associated with overall survival in breast cancer patients treated with bevacizumab. These results on the renovascular safety of bevacizumab in breast cancer patients showed that the prevalence of hypertension and proteinuria was high at baseline and, moreover, patients treated with bevacizumab frequently developed de novo hypertension and/or proteinuria. Finally, neither hypertension, nor proteinuria, neither at baseline, nor de novo, were associated with overall survival in our cohort of "real-life'' patients

Abstract 2825: Germline genetic variants in ANGPT1 &amp; 2 and FGF2 are associated with pathologic complete response to bevacizumab in breast cancer patients

Abstract Purpose: Vascular endothelial growth factor (VEGF) is a central mediator of angiogenesis in cancer and may be targeted by the monoclonal antibody bevacizumab (B). We have conducted a prospective phase II study using neoadjuvant B and chemotherapy (CT) in breast cancer patients and showed improved pathologic complete response (pCR) with the combination compared to the expected pCR with CT alone (41% vs. 25%, p=0.029 one sided). We evaluated baseline serum levels of ten angiogenesis-related proteins (ANG1, ANG2, bFGF, IL-1a, MMP-9, PDGF-BB, PECAM-1, Tie-2, VEGF and VEGFR2) and found that baseline Tie-2 and bFGF serum levels were associated with pCR. The goal of the current study is to explore the association of germline single-nucleotide polymorphisms (SNPs) to pCR obtained with bevacizumab therapy. Methods: Our original patient population consisted of 27 whites (EA) and 12 African Americans (AA) who received docetaxel/cyclophosphamide/bevacizumab and doxorubicin. Only 22 EA and 11 AA had buffy coat samples available for genotyping with the Illumina® HumanOmni2.5-8v1-1 BeadChip. We tested 555 SNPs with a minor allele frequency (MAF) of at least 5%, located in 10 angiogenesis-related genes. Results: Univariate analysis revealed that 73% AA patients achieved pCR compared to 27% EA (p=0.012) and that 54% of the patients with ductal carcinomas achieved pCR compared to 11% with lobular or poorly differentiated tumors (p=0.021). We therefore included race and cancer type as covariates in a logistic regression model testing for association between pCR and each of the 555 SNPs. There were five SNPs in ANGPT1, five in ANGPT2, and four in FGF2 that were associated with pCR (p&amp;lt;0.05). Because of the modest sample size, none of these SNPs reached levels of significance after adjusting for multiple comparisons. Conclusion: ANGPT1, ANGPT2 and FGF2 are promising targets for future research. SNP analysis results support our hypothesis that the interaction of the host's angiogenic profile and the type of cancer explains differences in clinical response to VEGF inhibition. Specifically, our work showed that variants of the ANGPT1, ANGPT2, and FGF2 genes or their respective proteins might render certain tumors more susceptible to targeting of VEGF.. Citation Format: Issam Makhoul, Robert Griffin, Stephen Erickson, Ishwori Dhakal, Venay R. Raj, Dorothy A. Graves, Jeannette Y. Lee, Mohammed S. Orloff, Eric R. Siegel, Susan A. Kadlubar. Germline genetic variants in ANGPT1 &amp; 2 and FGF2 are associated with pathologic complete response to bevacizumab in breast cancer patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2825. doi:10.1158/1538-7445.AM2014-2825

Results of the MARS study on the management of antiangiogenics’ renovascular safety in breast cancer.

e12504 Background: Anti-VEGF drugs (AVD) are widely used in cancer patients (pts). Hypertension (HTN) and proteinuria (Pu) are class-side-effects of AVD, related to the inhibition of the VEGF pathway. The MARS study has been conducted to assess the renovascular tolerance of these drugs in the clinical setting. Methods: This multicentric, prospective, observational study evaluated the renovascular safety of AVD in pts naive from any AVD, conducted in 7 centres in France, from 2009 to 2012, with a follow-up (f/u) of 1 year. Data collected included: gender, age, serum creatinine (SCr), diabetes, HTN, hematuria (Hu) and dipstick Pu, at baseline and at each visit. Results: 1,124 pts were included; 402 breast cancer (BC) pts received bevacizumab. Median age at inclusion was 55 years. Visceral, bone and cerebral metastasis frequencies were 74.7, 5.1 and 2.5%, respectively. HTN prevalences: 12.4%. Baseline renal assessment retrieved: Pu 23.9%, Hu 16.2%, mean aMDRD 96.4 ml/min/1.73m2 and 14 pts with aMDRD&lt;60. The incidence of de novo Pu and HTN during f/u was 61.7 and 16.8% (Table). 69.7 % of pts with Pu at inclusion improved or remained stable. Among pts with de novo Pu, 75.7% afterwards improved/normalized. No grade 4 Pu has been reported. Renal function remained stable with a mean aMDRD of 96.2 at the end of f/u. 7.4% had grade 2-3 SCr increase (no grade 3-4). No thrombotic micro-angiopathy (TMA) was reported. Conclusions: These results on the renovascular safety of bevacizumab in BC patients showed that 1) TMA is rare, 2) Grade 3 Pu developed in 4.6% of pts, with no grade 4, 3) less than 17% developed HTN, and 4) aMDRD was stable. Furthermore, in case of a renovascular effect, investigators followed the recommendations from the French Society of Nephrology (Halimi JM. Nephrol Ther 2008) and no treatment withdrawal for unmanageable renovascular toxicity occurred. [Table: see text]

Abstract P3-12-03: Combined targeting of HER2 and VEGFR2 for effective treatment of HER2-amplified breast cancer brain metastases.

Abstract Brain metastases remain a serious obstacle in the treatment of patients with human epidermal growth factor receptor-2 (HER2)-amplified breast cancer. Unlike HER2-amplified breast tumors growing in extra-cranial locations, brain metastases do not respond well to HER2 inhibitors and are often the reason for treatment failure. One of the major challenges in studying brain metastases is the lack of preclinical models. We developed a HER2-amplified mouse model of brain metastasis using an orthotopic xenograft of BT474 cells in mice. As seen in patients, the HER2 inhibitors trastuzumab and lapatinib failed to contain brain metastatic tumor growth. Based on previous findings from our laboratory suggesting a role of vascular endothelial growth factor (VEGF) in the resistance of HER2-overexpressing breast cancer brain metastases to trastuzumab, we combined HER2 inhibitors with the anti-VEGFR2 antibody DC101. The combination of either trastuzumab and DC101 or lapatinib and DC101 significantly slowed metastatic tumor growth in the brain, and resulted in a striking improvement in overall survival. The benefit is due largely to an anti-angiogenic effect. The combination of anti-HER2 and anti-VEGFR2 therapy reduced both the total and functional microvascular density in the brain metastatic tumors. Moreover, tumor tissues under combination therapy showed a marked increase in necrosis. Preclinical and clinical evidence suggest that the combination of trastuzumab and lapatinib is superior to either agent alone – though this has never been tested in the brain metastatic setting. We consistently observed increased phosphorylation of HER2 in breast tumor cells growing in the brain compared with the mammary fat pad. In addition, while short-term lapatinib treatment significantly reduced HER2 activation in the brain, it could do so only to the level of that observed in the untreated mammary fat pad - and this effect disappeared over time. We hypothesized that more pronounced HER2 inhibition would be beneficial to these brain metastases with increased HER2 activation. We show here a significant growth delay with the combination of the two HER2 inhibitors compared with monotherapy. Moreover, we found a dramatic brain metastatic tumor growth delay in mice treated with both HER2 inhibitors, trastuzumab and lapatinib, and DC101. The triple combination prolonged overall survival 5 times longer than control-treated mice. Brain metastasis from breast cancer is considered the “final frontier” of breast cancer research and treatment. Our findings support the clinical development of a three-drug regimen of trastuzumab, lapatinib and a VEGF pathway inhibitor for the treatment of HER2-amplified breast cancer brain metastases. While the anti-VEGF antibody bevacizumab in combination with trastuzumab and chemotherapy has shown some promise in HER2-positive metastatic breast cancer patient, there are no data on its efficacy in the context of brain metastases. A clinical trial is now recruiting patients to evaluate the efficacy of bevacizumab in breast cancer patients with active brain metastases, including its combination with trastuzumab in patients with HER2-positive disease. This trial may provide clinical evidence for the approach presented here. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-12-03.

Abstract CN07-01: Two-in-one antibody: Herceptin variants that target HER2 and VEGF

Abstract CN07-01: Two-in-one antibody: Herceptin variants that target HER2 and VEGF