Neoadjuvant treatment of breast cancer is applied to an increasing extent, but treatment response varies and side effects pose a challenge. The vitamin E isoform delta-tocotrienol might enhance the ...efficacy of chemotherapy and reduce the risk of side effects. The aim of this study was to investigate the clinical effect of delta-tocotrienol combined with standard neoadjuvant treatment and the possible association between detectable circulating tumor DNA (ctDNA) during and after neoadjuvant treatment with pathological treatment response. This open-label, randomized phase II trial included 80 women with newly diagnosed, histologically verified breast cancer randomized to standard neoadjuvant treatment alone or in combination with delta-tocotrienol. There was no difference in the response rate or frequency of serious adverse events between the two arms. We developed a multiplex digital droplet polymerase chain reaction (ddPCR) assay for the detection of ctDNA in breast cancer patients that targets a combination of two methylations specific for breast tissue (LMX1B and ZNF296) and one cancer specific methylation (HOXA9). The sensitivity of the assay increased when the cancer specific marker was combined with the ones specific to breast tissue (p < 0.001). The results did not show any association between ctDNA status and pathological treatment response, neither at midterm nor before surgery.
Treatment options in metastatic breast cancer are limited. New therapies preferable with predictive biomarkers are needed. The aim of these trials was to investigate if gene copy number of the ...topoisomerase 1 gene was predictive of response to the topoisomerase inhibitor irinotecan.
Two open-label, single-arm phase II studies including HER2 positive and negative patients were conducted. Patients were eligible for inclusion if the primary tumor or a metastatic lesion had increased expression of the topoisomerase 1 gene defined as a TOP1 gene copy number of ≥4 or a TOP1/CEN20 ratio of ≥2. Patients were treated with irinotecan +/- trastuzumab weekly for 4 weeks following 2 weeks break, until progression or unacceptable toxicities. Evaluation scans were performed every 6 weeks. Primary endpoint was clinical benefit rate defined as the fraction of patients with stable disease for ≥4 months.
The pre-planned number of 18 patients in each trial was not reached, thus no formal statistical analysis could be performed. Nine patients with HER2 negative disease and three patients with HER2 positive disease were included. Three patients obtained a partial remission and two patients had SD.
The trials did not include the planned number of patients. No association between gene copy number of the topoisomerase 1 gene and response to irinotecan could be proved, however a clinical benefit was found in 5/12 patients and in 2/3 patients with HER2 positive disease. This could call for further investigation of the drug in the metastatic setting, especially in HER2 positive BC.
Eudract registration numbers 2012-002348-26 and 2012-002347-23 . Registration date August 20th 2012.
Neratinib is an irreversible pan-HER tyrosine kinase inhibitor that inhibits PI3K/Akt and MAPK signaling pathways after HER2 receptor activation. The ExteNET study showed that neratinib significantly ...improved 5-year invasive disease-free survival (iDFS) in women who completed trastuzumab-based adjuvant therapy for early breast cancer (EBC). We assessed the prognostic and predictive significance of PIK3CA alterations in patients in ExteNET.
Participants were women aged ≥ 18 years (≥ 20 years in Japan) with stage 1-3c (modified to stage 2-3c in February 2010) operable breast cancer, who had completed (neo)adjuvant chemotherapy plus trastuzumab ≤ 2 years before randomization, with no evidence of disease recurrence or metastatic disease at study entry. Patients were randomized to oral neratinib 240 mg/day or placebo for 1 year. Formalin-fixed, paraffin-embedded primary tumor specimens underwent polymerase chain reaction (PCR) PIK3CA testing for two hotspot mutations in exon 9, one hot-spot mutation in exon 20, and fluorescence in situ hybridization (FISH) analysis for PIK3CA amplification. The primary endpoint (iDFS) was tested with log-rank test and hazard ratios (HRs) estimated using Cox proportional-hazards models.
Among the intent-to-treat population (n = 2840), tumor specimens were available for PCR testing (991 patients) and PIK3CA FISH (702 patients). Overall, 262 samples were PIK3CA altered: 201 were mutated (77%), 52 (20%) were amplified, and 9 (3%) were mutated and amplified. iDFS was non-significantly worse in placebo-treated patients with altered vs wild-type PIK3CA (HR 1.34; 95% CI 0.72-2.50; P = 0.357). Neratinib's effect over placebo was significant in patients with PIK3CA-altered tumors (HR 0.41; 95% CI 0.17-0.90, P = 0.028) but not PIK3CA wild-type tumors (HR 0.72; 95% CI 0.36-1.41; P = 0.34). The interaction test was non-significant (P = 0.309).
Although there was a greater absolute risk reduction associated with neratinib treatment of patients with PIK3CA-altered tumors in ExteNET, current data do not support PIK3CA alteration as a predictive biomarker of response to neratinib in HER2-positive EBC.
ClinicalTrials.gov , NCT00878709 . Trial registered April 9, 2009.
Purpose
Anthracyclines remain a cornerstone in the treatment of primary and advanced breast cancer (BC). This study has evaluated the predictive value of a multigene mRNA-based drug response ...predictor (DRP) in the treatment of advanced BC with epirubicin. The DRP is a mathematical method combining in vitro sensitivity and gene expression with clinical genetic information from > 3000 clinical tumor samples.
Methods
From a DBCG cohort, 140 consecutive patients were treated with epirubicin between May 1997 and November 2016. After patient informed consent, mRNA was isolated from archival formalin-fixed paraffin-embedded primary breast tumor tissue and analyzed using Affymetrix arrays. Using time to progression (TTP) as primary endpoint, the efficacy of epirubicin was analyzed according to DRP combined with clinicopathological data collected retrospectively from patients’ medical records. Statistical analysis was done using Cox proportional hazards model stratified by treatment line.
Results
Median TTP was 9.3 months. The DRP was significantly associated to TTP (
P
= 0.03). The hazard ratio for DRP scores differing by 50 percentage points was 0.55 (95% CI –0.93, one-sided). A 75% DRP was associated with a median TTP of 13 months compared to 7 months following a 25% DRP. Multivariate analysis showed that DRP was independent of age and number of metastases.
Conclusion
The current study prospectively validates the predictive capability of DRP regarding epirubicin previously shown retrospectively allowing the patients predicted to be poor responders to choose more effective alternatives. Randomized prospective studies are needed to demonstrate if such an approach will lead to increased overall survival.
Purpose
Measurement of human epidermal growth factor receptor 2 (HER2) gene amplification in cell-free DNA (cfDNA) is an evolving technique in breast cancer, enabling liquid biopsies and treatment ...monitoring. The present study investigated the dynamics of plasma HER2 gene copy number and amplification in cfDNA during neoadjuvant chemotherapy.
Patients and methods
The study included 50 patients from a prospective cohort analyzed during neoadjuvant chemotherapy. Fifty healthy women with no history of cancer served as control group and 15 patients with metastatic breast cancer were used to validate the assay. Total cfDNA and HER2 gene amplification were measured by quantitative real-time polymerase chain reaction.
Results
Plasma HER2 gene copy number (
p
= 0.794), HER2 gene amplification (
p
= 0.127) and total cfDNA (
p
= 0.440) did not differ significantly from the levels in the control group. Eighteen patients (36 %) obtained pathological complete response (pCR). HER2 gene copy number before the operation was significantly higher than the baseline level (
p
< 0.0001), but there was no difference between patients with and without pCR (
p
= 0.569). Likewise, there was no difference in plasma HER2 gene amplification between tissue HER2-positive and -negative patients (
p
= 0.754).
Conclusions
The results indicate that neither total cfDNA nor HER2 gene copy number is elevated in primary breast cancer patients compared to healthy controls. The level of both parameters increased during neoadjuvant chemotherapy, but without any relation to treatment effect. There was no indication of plasma HER2 gene amplification in the HER2-positive patients in the neoadjuvant setting.
Placenta growth factor (PlGF) and vascular endothelial growth factor A (VEGF-A) are angiogenic growth factors interacting competitively with the same receptors. VEGF-A is essential in both normal and ...pathologic conditions, but the functions of PlGF seem to be restricted to pathologic conditions such as ischemic heart disease, arthritis and tumor growth. Angiogenesis is a complex process with several growth factors involved. Because PlGF modulates VEGF-A responses, we investigated their mutual relationship and impact on breast cancer prognosis. Quantitative PlGF and VEGF-A levels were measured in 229 tumor tissue specimen from primarily operated patients with unilateral breast cancer. Non-malignant breast tissue was also dissected near the tumor and quantitative measurements were available for 211 patients. PlGF and VEGF-A protein levels in homogenized tissue lysates were analyzed using the Luminex system. We found significantly higher median levels of PlGF and VEGF-A in tumor tissue compared to non-malignant tissue (PlGF: 69.8 vs. 31.4 pg/mg,
p
< 0.001 and VEGF-A: 1148.2 vs. 163.5 pg/mg,
p
< 0.001). PlGF and VEGF-A were correlated in both malignant tissue (
r
= 0.41,
p
< 0.001) and in non-malignant tissue (
r
= 0.69,
p
< 0.001). The proportion of node positive patients was higher with high PlGF expression (61.4%) than with low PlGF expression (45.6%) in tumor tissue,
p
= 0.024. High levels of PlGF and VEGF-A in tumor tissue were associated with significant shorter recurrence-free survival (RFS) in both univariate analysis (PlGF:
p
= 0.023; VEGF-A:
p
= 0.047) and in multivariate analysis (PlGF:
p
= 0.026; VEGF-A:
p
= 0.036). Neither PlGF nor VEGF-A expression in non-malignant tissue were predictors for RFS. In conclusion, our results support the mutual relationship between PlGF and VEGF-A and encourage further investigations as prognostic markers in breast cancer patients.
Background
Fulvestrant is a selective oestrogen receptor (ER) degrader used as monotherapy and combination therapy for ER positive HER2 negative advanced breast cancer (ABC) in postmenopausal women. ...The drug response predictor (DRP), is a mathematical algorithm based on the expression of multiple genes in the tumour. The fulvestrant DRP algorithm has previously shown effect in BC. In this study, we investigated the DRP’s potential in predicting fulvestrant benefit.
Method
Among 695 patients with ABC prospectively included in a Danish Breast Cancer Cooperative Group (DBCG) cohort we retrospectively included 226 patients who received fulvestrant as monotherapy. The DRP result was based on mRNA extracted from tumour biopsies and analysed using Affymetrix array. Primary endpoint was time to progression (TTP).
Results
For patients who received fulvestrant in line one to four and were previously unexposed to adjuvant endocrine therapy, we identified a hazard ratio (HR) of 0.44 (90% confidence interval (90% CI) upper limit of 1.08, one sided
p
= 0.066) for a predicted positive vs negative outcome. A weaker association was seen when including patients exposed to adjuvant endocrine treatment or received fulvestrant in fifth or later lines. Exploratory analyses showed that the DRP was efficient when using recent biopsies for DRP estimate and among recently treated patients.
Conclusion
The DRP showed a potential in predicting fulvestrant treatment but was not significant in the overall analysis. Use of older biopsies, long-term endocrine treatment and multiple therapies between biopsy used for analysis and fulvestrant treatment, probably affect the predictive accuracy.
Abstract Aim: Attempts have been made to use CTC values for interpretation of treatment response and to guide change of chemotherapy by using a static cut-off of 5 CTC to stratify patients in ...favourable or unfavourable responders. We propose a new approach to interpret treatment effect using significant changes in CTC values (SCV-limits ) as grouping parameter for responders and non-responders to chemotherapy among metastatic breast cancer (mBC) patients. Method: CTC were analysed using the CellSearch System in blood from 47 mBC patients before the start of new chemotherapy and before the third cycle of therapy. The new and old approach to interpret changes in CTC values were compared in relation to progression free survival (PFS). Results: The new approach using significant CTC change ( P = .032) and the old approach using static cut-off ( P > .001) correlated significantly with PFS using a cohort of 47 patients. Conclusion: We propose a new approach to interpret significant changes between baseline and follow-up CTC values as a tool for assessing treatment effect in mBC. Our approach stratified patients in new risk groups that were stratified significantly with respect to PFS. More patients are needed to balance the size of the risk groups for better comparison to the existing approach based on a 5 CTC cut-off.
The present study aimed to evaluate the extent of loss in bone mineral density (BMD) during neoadjuvant and adjuvant chemotherapy for early stage breast cancer. A retrospective cohort study was ...conducted to quantify the loss of BMD one year following the start of chemotherapy and to identify potential risk factors of excessive BMD loss. Based on DXA-scans prior to and one year following chemotherapy, the loss of BMD was evaluated in early stage breast cancer patients treated from January 2012 to December 2014. A total of 492 patients received either eight cycles of neoadjuvant or six cycles of adjuvant chemotherapy. The final analysis included 152 patients with two DXA-scans. The patients had a significant loss of BMD in the hip -0.0124 g/cm
(95% confidence interval (CI) -0.018; -0.007) P<0.001 and in the lumbar spine -0.029 g/cm
(95% CI: -0.036; -0.023) P<0.001 corresponding to a change of -1, 3 and -2, 9%, respectively. Premenopausal women had a significant loss of BMD in the lumbar spine -0.045 g/cm
equivalent to -4.3%, which was significantly increased compared with postmenopausal women (P<0.001) in the univariate analysis, whereas only a trend persisted in the multivariate analysis (P=0.60). There was no significant difference in BMD loss (lumbar spine P=0.176) between patients receiving adjuvant and neoadjuvant chemotherapy. In conclusion, neoadjuvant and adjuvant chemotherapy is associated with significant BMD loss in both hip and lumbar spine. Furthermore, the results of the present study indicate that premenopausal women have a pronounced BMD loss in the lumbar spine. Further studies investigating osteoporosis prophylaxis in premenopausal patients are warranted.
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