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.

Download Full-text

Neoadjuvant Chemotherapy Induces the Appearance of New Copy Number Aberrations in Breast Tumor and is Associated with Metastasis

Current Cancer Drug Targets ◽

10.2174/1568009620666200506104523 ◽

2020 ◽

Vol 20 (9) ◽

pp. 681-688

Author(s):

Nikolai V. Litviakov ◽

Marina K. Ibragimova ◽

Matvey M. Tsyganov ◽

Artem V. Doroshenko ◽

Eugeniy Y. Garbukov ◽

...

Keyword(s):

Breast Cancer ◽

Neoadjuvant Chemotherapy ◽

Copy Number ◽

Breast Cancer Patients ◽

Free Survival ◽

Luminal B ◽

Cell Clones ◽

Genetic Landscape ◽

Intelligent Approach

Background: In this study, we examined the CNA-genetic landscape (CNA – copy number aberration) of breast cancer prior to and following neoadjuvant chemotherapy (NAC) and correlated changes in the tumor landscape with chemotherapy efficiency as well as metastasis-free survival. Objective: Breast cancer patients (n = 30) with luminal B molecular subtypes were treated with anthracycline- based therapy. Methods: To study CNAs in breast tumors, microarray analysis was performed. Results: Three effects of NAC on tumor CNA landscape were identified: 1 – the number of CNA-bearing tumor clones decreased following NAC; 2 – there were no alterations in the number of CNA-containing clones after NAC; 3 – the treatment with NAC increased the number of CNA-bearing clones (new clones appeared). All NAC-treated patients who had new tumor clones with amplification (20%) had a 100% likelihood of metastasis formation. In these cases, NAC contributed to the emergence of potential metastatic clones. Our study identified the following loci – 5p, 6p, 7q, 8q, 9p, 10p, 10q22.1, 13q, 16p, 18Chr and 19p – that were amplified during the treatment with NAC and may be the markers of potential metastatic clones. In other patients who showed total or partial elimination of CNA-bearing cell clones, no new amplification clones were observed after NAC, and no evidence of metastases was found with follow-up for 5 years (р = 0.00000). Conclusion: Our data suggest that the main therapeutic result from NAC is the elimination of potential metastatic clones present in the tumor before treatment. The results showed the necessity of an intelligent approach to NAC to avoid metastasis stimulation.

Download Full-text

LINAC-based stereotactic radiosurgery/radiotherapy for brain metastases in patients with breast cancer

Journal of Radiotherapy in Practice ◽

10.1017/s1460396921000029 ◽

2021 ◽

pp. 1-9

Author(s):

Ankita Gupta ◽

Budhi Singh Yadav ◽

Nagarjun Ballari ◽

Namrata Das ◽

Ngangom Robert

Keyword(s):

Breast Cancer ◽

Overall Survival ◽

Brain Metastases ◽

Stereotactic Radiosurgery ◽

Progression Free Survival ◽

Rank Test ◽

Karnofsky Performance Score ◽

Breast Cancer Patients ◽

Free Survival ◽

Prior Surgery

Abstract Background: Brain metastases (BM) are common in patients with HER2-positive and triple-negative breast cancer. In this study we aim to report clinical outcomes with LINAC-based stereotactic radiosurgery/radiotherapy (SRS/SRT) for BM in patients of breast cancer. Methods: Clinical and dosimetric records of breast cancer patients treated for BM at our institute between May, 2015 and December, 2019 were retrospectively reviewed. Patients of previously treated or newly diagnosed breast cancer with at least a radiological diagnosis of BM; 1–4 in number, ≤3·5 cm in maximum dimension, with a Karnofsky Performance Score of ≥60 were taken up for treatment with SRS. SRT was generally considered if a tumour was >3·5 cm in diameter, near a critical or eloquent structure, or if the proximity of moderately sized tumours would lead to dose bridging in a single-fraction SRS plan. The median prescribed SRS dose was 15 Gy (range 7–24 Gy) and SRT dose was 27 Gy in 3 fractions. Clinical assessment and MR imaging was done at 6 weeks post-SRS and then every 3 months thereafter. Intracranial progression-free survival (PFS) and overall survival (OS) were calculated using Kaplan–Meier method and subgroups were compared using log rank test. Results: Total, 40 tumours were treated in 31 patients. The median tumour diameter was 2·3 cm (range 1·0–4·6 cm). SRS and SRT were delivered in 27 and 4 patients, respectively. SRS/SRT was given as a boost to whole brain radiotherapy (WBRT) in four patients and as salvage for progression after WBRT in six patients. In general, nine patients underwent prior surgery. The median follow-up was 7·9 months (0·2–34 months). Twenty (64·5%) patients developed local recurrence, 10 (32·3%) patients developed distant intracranial relapse and 7 patients had both local and distant intracranial relapse. The estimated local control at 6 months and 1 year was 48 and 35%, respectively. Median intracranial progression free survival (PFS) was 3·73 months (range 0·2–25 months). Median intracranial PFS was 3·02 months in patients who received SRS alone or as boost after WBRT, while it was 4·27 months in those who received SRS as salvage after WBRT (p = 0·793). No difference in intracranial PFS was observed with or without prior surgery (p = 0·410). Median overall survival (OS) was 21·7 months (range 0·2–34 months) for the entire cohort. Patients who received prior WBRT had a poor OS (13·31 months) as compared to SRS alone (21·4 months; p = 0·699). Conclusion: In patients with BM after breast cancer SRS alone, WBRT + SRS and surgery + SRS had comparable PFS and OS.

Download Full-text

Randomized cooperative study of perioperative chemotherapy in breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.1995.13.11.2712 ◽

1995 ◽

Vol 13 (11) ◽

pp. 2712-2721 ◽

Cited By ~ 22

Author(s):

M R Sertoli ◽

P Bruzzi ◽

P Pronzato ◽

P Queirolo ◽

D Amoroso ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Preliminary Evidence ◽

Breast Cancer Patients ◽

Free Survival ◽

Node Negative ◽

Significant Survival ◽

Significant Difference ◽

Estrogen Receptor Negative

PURPOSE The aim of this multicentric randomized trial was to determine whether reducing the interval between surgery and chemotherapy improves the outcome of breast cancer patients. PATIENTS AND METHODS Between June 1985 and July 1992, 600 breast cancer patients, clinical stages T1-3A,N0-2,M0 were randomly assigned to a perioperative cycle (PC) of cyclophosphamide 600 mg/m2, epidoxorubicin 60 mg/m2, and fluorouracil 600 mg/m2 (CEF). Node-negative (N-) patients did not receive any further treatment. Node positive (N+) patients received 11 cycles if previously given PC, or 12 cycles of CEF alternated with cyclophosphamide 600 mg/m2, methotrexate 40 mg/m2, and fluorouracil 600 mg/m2 (CMF). In addition, N+ patients received concomitant or sequential 5-year tamoxifen therapy. RESULTS At a median follow-up duration of 5.7 years, no significant difference in survival (88% v 84%, P = .3) between the two treatment arms was seen. However, a difference of borderline significance in relapse-free survival (RFS; 76% v 70%, P = .053) was evident. A significant survival advantage for the PC arm was detected only in the estrogen receptor-negative (ER-) patients (P = .003). RFS was significantly improved in N- patients, postmenopausal patients, and ER- patients. Multivariate analyses show that pathologic tumor size, nodal status, receptor status, and treatment (only in ER- patients) are significantly correlated with survival and RFS. PC toxicity did not influence wound healing. CONCLUSION This study provides preliminary evidence that PC positively affects relapse rate and survival in some subgroups, namely, ER- patients.

Download Full-text

Conversion Chemotherapy With a Modified FLOX Regimen for Borderline or Unresectable Liver Metastases From Colorectal Cancer: An Alternative for Limited-Resources Settings

Journal of Global Oncology ◽

10.1200/jgo.19.00180 ◽

2019 ◽

pp. 1-6

Author(s):

Renata Colombo Bonadio ◽

Paulo Henrique Amor Divino ◽

Jorge Santiago Madero Obando ◽

Karolina Cayres Alvino Lima ◽

Débora Zachello Recchimuzzi ◽

...

Keyword(s):

Colorectal Cancer ◽

Liver Metastases ◽

Median Overall Survival ◽

Low Cost ◽

Progression Free Survival ◽

Hazard Ratio ◽

R0 Resection ◽

Free Survival ◽

Unresectable Liver Metastases

PURPOSE Conversion chemotherapy is often used for borderline or unresectable (B/U) liver metastases from colorectal cancer (CRC) with the aim of achieving resectability. Although intensive and costly regimens are often used, the best regimen in this scenario remains unclear. We aimed to evaluate the outcomes of patients with B/U liver metastases from CRC treated with conversion chemotherapy with the modified fluorouracil, leucovorin, and oxaliplatin (mFLOX) regimen followed by metastasectomy. METHODS We performed a single-center retrospective analysis of patients with B/U liver metastases from CRC treated with chemotherapy with the mFLOX regimen followed by surgery. B/U disease was defined as at least one of the following: more than four lesions, involvement of hepatic artery or portal vein, or involvement of biliary structure. RESULTS Fifty-four consecutive patients who met our criteria for B/U liver metastases were evaluated. Thirty-five patients (64%) had more than four liver lesions, 16 (29%) had key vascular structure involvement, and 16 (29%) had biliary involvement. After chemotherapy, all patients had surgery and 42 (77%) had R0 resection. After a median follow-up of 37.2 months, median progression-free survival (PFS) was 16.9 months and median overall survival (OS) was 68.3 months. R1-R2 resections were associated with worse PFS and OS compared with R0 resection (PFS: hazard ratio, 2.65; P = .007; OS: hazard ratio, 2.90; P = .014). CONCLUSION Treatment of B/U liver metastases from CRC with conversion chemotherapy using mFLOX regimen followed by surgical resection was associated with a high R0 resection rate and favorable survival outcomes. On the basis of our results, we consider mFLOX a low-cost option for conversion chemotherapy among other options that have been proposed.

Download Full-text

Cetuximab and chemotherapy in the treatment of patients with initially “nonresectable” colorectal (CRC) liver metastases: Long-term follow-up of the CELIM trial.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.3538 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 3538-3538 ◽

Cited By ~ 2

Author(s):

Gunnar Folprecht ◽

Thomas Gruenberger ◽

Wolf Bechstein ◽

Hans-Rudolf Raab ◽

Juergen Weitz ◽

...

Keyword(s):

Liver Metastases ◽

Tumor Response ◽

Progression Free Survival ◽

R0 Resection ◽

Term Survival ◽

Free Survival ◽

Long Term Follow Up ◽

Clinical Trial Information

3538 Background: CRC liver metastases can be resected after downsizing with intensive chemotherapy schedules, with a strong correlation between the response and resection rates. Cetuximab plus chemotherapy has been shown to increase the rates of tumor response and resection of liver metastases. (Van Cutsem et al, JCO 2011). Methods: Patients (pts) with technically non-resectable and/or with > 4 liver metastases were randomized to treatment with FOLFOX/cetuximab (arm A) or FOLFIRI/cetuximab (arm B) and evaluated regarding resectability every 2 months. Resection was offered to all patients who became resectable during the study. K-ras and b-raf status were retrospectively evaluated. Data on tumor response and resection were reported earlier (Folprecht et al, Lancet Oncol 2010). Overall and progression free survival were analyzed in December 2012. Results: Between Dec 2004 and March 2008, 56 pts were randomized to arm A, 55 to arm B. For the current analysis, 109 pts were evaluable for overall survival (OS), and 106 patients for PFS. The median OS was 35.7 [95% CI: 27.2-44.2] months (arm A: 35.8 [28.1-43.6], arm B: 29.0 [16.0-41.9], HR 1.03 [0.66-1.61], p=0.9). The median PFS was 10.8 [9.3-12.2] months (Arm A: 11.2 [7.2-15.3], Arm B: 10.5 [8.9-12.2], HR 1.18 [0.79-1.74], p=0.4). Patients with R0 resection had a better OS (median: 53.9 [35.9-71.9] mo) than patients without R0 resection (27.3 [21.1-33.4] mo, p=0.002) and a better PFS (median 15.4 [11.4-19.5] and 8.9 [6.7-11.1] mo in R0 resected and not R0 resected pts, p<0.001). The 5 year survival in R0 resected patients is 46.2% [29.5-62.9%]. Conclusions: This study confirmed a favourable long term survival of patients with initially “nonresectable” CRC liver metastases treated in a multidisciplinary approach of neoadjuvant chemotherapy with cetuximab and subsequent metastasectomy in pts who became resectable. Clinical trial information: NCT00153998. [Table: see text]

Download Full-text

An update on BREAK-3, a phase III, randomized trial: Dabrafenib (DAB) versus dacarbazine (DTIC) in patients with BRAF V600E-positive mutation metastatic melanoma (MM).

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.9013 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 9013-9013 ◽

Cited By ~ 45

Author(s):

Axel Hauschild ◽

Jean Jacques Grob ◽

Lev V. Demidov ◽

Thomas Jouary ◽

Ralf Gutzmer ◽

...

Keyword(s):

Median Overall Survival ◽

Braf Inhibitor ◽

Progression Free Survival ◽

Braf V600e ◽

Phase Iii ◽

Primary Analysis ◽

Free Survival ◽

Independent Review ◽

Clinical Trial Information

9013 Background: Dabrafenib is a selective BRAF inhibitor with demonstrated efficacy in BRAF V600E-positive mutation in MM. The primary analysis of BREAK-3 (NCT01227889) compared progression-free survival (PFS) in patients (pts) with BRAF V600E-positive mutation MM treated with dabrafenib or DTIC. Methods: Median PFS for dabrafenib of 5.1 months (mo) and study methods were previously described (Hauschild A, et al. Lancet. 2012,380:358–365). Independent review ended at the primary analysis. PFS was updated in Jun 2012 at median follow-up of 10.5 mo for dabrafenib (67% of PFS events), and 9.9 mo for DTIC. Median overall survival (OS) was not reached, so another analysis of OS and safety was performed with data as of Dec 2012, at which time the median follow-up was 15.2 (dabrafenib) and 12.7 (DTIC) mo. PFS of subjects who crossed over was also evaluated at that time. Results: PFS hazard ratio was 0.37 [95% CI; 0.23, 0.57]; median PFS was 6.9 mo dabrafenib and 2.7 mo DTIC. In Dec 2012, 36/63 DTIC pts crossed over; median PFS was 4.3 [95% CI; 4.1, 6.1] mos. OS is presented in the Table.The four most common adverse events (AE) on the dabrafenib arm were hyperkeratosis (39%), headache (35%), arthralgia (35%), and pyrexia (32%). Serious AEs ≥ 5% on the dabrafenib arm included cutaneous squamous cell carcinoma/keratoacanthoma (10%) and pyrexia (5%). Conclusions: Longer follow-up confirms the benefits of dabrafenib on PFS and response rate. Median OS in the dabrafenib arm was over 18 mo and over 15 mo in the DTIC arm. OS results are confounded by crossover of DTIC pts to dabrafenib and likely by subsequent therapy after progression. The effects of subsequent therapy results will be investigated. The safety profile had no significant changes. Clinical trial information: NCT01227889. [Table: see text]

Download Full-text

Level of activated circulating endothelial cells to predict progression-free survival of Anlotinib treatment in patients with NSCLC: Analysis on ALTER-0303 study.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e20530 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e20530-e20530 ◽

Cited By ~ 1

Author(s):

Kai LI ◽

Jing Wang ◽

Xinyue Wang ◽

Zhujun Liu ◽

Cuigui Zhang ◽

...

Keyword(s):

Endothelial Cells ◽

Initial Period ◽

Progression Free Survival ◽

Circulating Endothelial Cells ◽

Free Survival ◽

Time Points ◽

Potential Biomarker ◽

Nsclc Patients ◽

Clinical Trial Information

e20530 Background: Activated circulating endothelial cells (aCECs) have been indicated as a potential biomarker of angiogenesis in a variety of cancers. Several studies have revealed that aCECs may reflect the extent of tumor angiogenesis, and the level of aCECs counts may has correlation with progression-free survival (PFS) in anti-angiogenesis therapy on NSCLC patients. Therefore, we investigated the association between aCECs and PFS of Anlotinib treatment in ALTER-0303 study. Methods: NSCLC patients with aCECs counts in ALTER-0303 study were observed. Samples were prospectively collected at six time points: before treatment (baseline), on the 7th, 15th, 21th, 42th, 63thday of Anlotinib treatment. aCECs was identified by Flow cytometry (FCM). The prognostic value of aCECs counts was analyzed and, the patients were stratified according to their ratio of the minimum aCECs counts in all time points and counts on baseline (aCECs min/baseline) as <1 and ≥1. Results: Forty-nine patients were included of which 35 and 14 had an aCECs min/baseline<1 and ≥1, respectively in Anlotinib arm. Median follow-up was 8.6 months. In univariate survival analysis, patients with min/baseline<1 had longer PFS [HR=0.439, 95% CI (0.211-0.912), P = 0.023], the median PFS for the patients with aCECs min/baseline <1 and ≥1 were 193 days and 124 days, respectively (shown in Table). However, there were no significant relation between PFS and such aCECs min/baseline ratio found in control arm of ALTER-0303 study. Conclusions: A decrease of aCECs counts from baseline during an initial period of Anlotinib therapy may predict longer PFS and good response in NSCLC patients. Information: NCT02029209, NCT02388919 Clinical trial information: NCT02029209. [Table: see text]

Download Full-text

Subsequent pregnancy and long-term safety from breast cancer patients.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e13575 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e13575-e13575

Author(s):

Yunyeong Kim ◽

Minsun Kang ◽

Jaehun Jung ◽

Eun Kyung Cho ◽

Heung Kyu Park ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative ◽

Disease Free Survival ◽

Breast Cancer Patients ◽

Free Survival ◽

Tumor Subtypes ◽

Study Population ◽

Disease Free

e13575 Background: Long-term safety of pregnancy after breast cancer still remained controversial, especially according to tumor subtypes. Prior results of other studies have limitations of short follow-up periods or small groups. Methods: We analyzed a population-based retrospective cohort data extracted from a random sample of 50% of women aged between 20 and 60 years who were diagnosed with breast cancer from 2002 to 2017 in the Korean National Health Insurance Service database. Propensity score matching analysis for age and Charlson Comorbidity Index (CCI) variables was performed for pregnant groups and non-pregnant groups with the same type of hormone therapy, chemotherapy and surgery. Study population was categorized to 4 biologic subgroups by the combination of hormone therapy, chemotherapy and target therapy. In this observational study, 1,566 patients with pregnancy after breast cancer were matched (1:2) to 2,462 non-pregnant patients of similar characteristics, adjusting for guaranteed bias. The matched patients were followed up to 7 years, or disease and mortality occurrence after the diagnosis of breast cancer. Survival estimates were calculated using the Kaplan-Meier analysis, groups were compared with the log-rank test. Results: Mean time from diagnosis to pregnancy was 3.4 years in study population. At a follow-up of 7 years after pregnancy, no inferiority in disease-free survival and overall survival was observed in pregnant patients factoring in treatment bias. In sub-analysis according to tumor subtypes, no difference in disease-free survival was observed between pregnant and non-pregnant patients in HR-positive and triple negative subgroup ( p= 0.088, p= 0.048, respectively). Likewise, no overall survival difference was observed in ER-positive patients and triple negative patients ( p= 0.05∼0.73, p= 0.03∼0.09, respectively). Conclusions: Our observational data provides reassuring evidence on long-term safety of pregnancy in young breast cancer patients, regardless of tumor subtypes.

Download Full-text