Recent clinical results support the use of new immune checkpoint blockers (ICB), such as anti-PD-1 (e.g. nivolumab and pembrolizumab) and anti-PD-L1 antibodies. Radiological evaluation of ICB ...efficacy during therapy is challenging due to tumor immune infiltration. Changes of circulating tumor DNA (ctDNA) levels during therapy could be a promising tool for very accurate monitoring of treatment efficacy, but data are lacking with ICB.
This prospective pilot study was conducted in patients with nonsmall cell lung cancer, uveal melanoma, or microsatellite-instable colorectal cancer treated by nivolumab or pembrolizumab monotherapy at Institut Curie. ctDNA levels were assessed at baseline and after 8 weeks (w8) by bidirectional pyrophosphorolysis-activated polymerization, droplet digital PCR or next-generation sequencing depending on the mutation type. Radiological evaluation of efficacy of treatment was carried out by using immune-related response criteria.
ctDNA was detected at baseline in 10 out of 15 patients. At w8, a significant correlation (r = 0.86; P = 0.002) was observed between synchronous changes in ctDNA levels and tumor size. Patients in whom ctDNA levels became undetectable at w8 presented a marked and lasting response to therapy. ctDNA detection at w8 was also a significant prognostic factor in terms of progression-free survival (hazard ratio = 10.2; 95% confidence interval 2.5–41, P < 0.001) and overall survival (hazard ratio = 15; 95% confidence interval 2.5–94.9, P = 0.004).
This proof-of-principle study is the first to demonstrate that quantitative ctDNA monitoring is a valuable tool to assess tumor response in patients treated with anti-PD-1 drugs.
Several expression array studies identified molecular apocrine breast cancer (BC) as a subtype that expresses androgen receptor (AR) but not estrogen receptor α. We carried out a multicentre ...single-arm phase II trial in women with AR-positive, estrogen, progesterone receptor and HER2-negative (triple-negative) metastatic or inoperable locally advanced BC to assess the efficacy and safety of abiraterone acetate (AA) plus prednisone.
Patients with a metastatic or locally advanced, centrally reviewed, triple-negative and AR-positive (≥10% by immunohistochemistry, IHC) BC were eligible. Any number of previous lines of chemotherapy was allowed. AA (1000 mg) was administered once a day with prednisone (5 mg) twice a day until disease progression or intolerance. The primary end point was clinical benefit rate (CBR) at 6 months defined as the proportion of patients presenting a complete response (CR), partial response (PR) or stable disease (SD) ≥6 months. Secondary end points were objective response rate (ORR), progression-free survival (PFS) and safety.
One hundred and forty-six patients from 27 centres consented for IHC central review. Of the 138 patients with sufficient tissue available, 53 (37.6%) were AR-positive and triple-negative, and 34 of them were included from July 2013 to December 2014. Thirty patients were eligible and evaluable for the primary end point. The 6-month CBR was 20.0% 95% confidence interval (CI) 7.7%–38.6%, including 1 CR and 5 SD ≥6 months, 5 of them still being under treatment at the time of analysis (6.4+, 9.2+, 14.5+, 17.6+, 23.4+ months). The ORR was 6.7% (95% CI 0.8%–22.1%). The median PFS was 2.8 months (95% CI 1.7%–5.4%). Fatigue, hypertension, hypokalaemia and nausea were the most common drug-related adverse events; the majority of them being grade 1 or 2.
AA plus prednisone treatment is beneficial for some patients with molecular apocrine tumours and five patients are still on treatment.
NCT01842321.
Abstract As a result of recent progress in detection techniques, circulating tumor DNA (ctDNA) and circulating tumor cells (CTC) can now be accurately detected in the blood of most cancer patients. ...While these new biomarkers can provide a better understanding of key biological mechanisms underlying cancer growth and dissemination, they also open up a wide range of possible clinical applications in medical oncology, radiation oncology and surgical oncology. In this review, we summarize the results obtained with ctDNA and CTC together with their potential future clinical applications in the field of surgical oncology, with particular focus on the perioperative setting of various types of cancer. These applications include, but are not limited to, cancer screening, early diagnosis, prognostic assessment, evaluation and management of preoperative systemic or local therapies, post-surgical detection of minimal residual disease and early detection of cancer relapse.
Trastuzumab improves the outcome of women with HER2 positive breast cancer. We aimed to assess whether trastuzumab decreases the detection rate of circulating tumor cells (CTCs) in women with high ...risk, HER2 nonamplified, early breast cancer.
The EORTC 90091-10093 BIG 1–12 Treat CTC is a phase II trial, conducted in 70 hospitals and 6 CTC laboratories across 5 European countries. Patients with centrally confirmed HER2 nonamplified breast cancer and ≥1 centrally confirmed CTC per 15ml of blood by CellSearch® following surgery and (neo)adjuvant chemotherapy were randomized (1:1) to 6 cycles of trastuzumab intravenously versus 18weeks of observation. Randomization was stratified for center, locally confirmed estrogen receptor status and adjuvant versus neoadjuvant chemotherapy. The primary end point was rate of detection of ≥1 CTC per 15ml of blood at week 18. Secondary end points were invasive disease-free survival (iDFS) and cardiac safety.
Between 30 April 2013 and 17 October 2016, 1317 patients were screened; 95 (7.2%) had detectable CTC(s), and 63 (4.8%) were randomized to trastuzumab (n=31) or observation (n=32). Fifty-eight patients were assessable for the primary end point, 29 in each arm. In 9 of the 58 patients, CTC(s) were still detected at week 18:5 in the trastuzumab and 4 in the observation arm (one-sided Fisher’s exact test, P=0.765). An Independent Data Monitoring Committee recommended stopping further accrual for futility for the primary end point. Median follow-up at database lock was 13months (IQR 4–16.5). The 1-year iDFS was 93.8% (95% CI 77.3–98.4) in the observation versus 84.8% (95% CI 63.4–94.2) in the trastuzumab arm. No grade 2–4 cardiac events were observed in the trastuzumab arm.
Trastuzumab does not decrease the detection rate of CTCs in HER2 nonamplified, nonmetastatic breast cancer.
We present a pooled analysis of predictive and prognostic values of circulating tumour cells (CTC) and circulating endothelial cells (CEC) in two prospective trials of patients with inflammatory ...breast cancer (IBC) treated with neoadjuvant chemotherapy combined with neoadjuvant and adjuvant bevacizumab.
Nonmetastatic T4d patients were enrolled in two phase II multicentre trials, evaluating bevacizumab in combination with sequential neoadjuvant chemotherapy of four cycles of FEC followed by four cycles of docetaxel in HER2-negative tumour (BEVERLY-1) or docetaxel and trastuzumab in HER2-positive tumour (BEVERLY-2). CTC and CEC were detected in 7.5 and 4ml of blood, respectively, with the CellSearch System.
From October 2008 to September 2010, 152 patients were included and 137 were evaluable for CTC and CEC. At baseline, 55 patients had detectable CTC (39%). After four cycles of chemotherapy, a dramatic drop in CTC to a rate of 9% was observed (P<0.01). Pathological complete response (pCR) rate was 40%. No correlation was found between CTC or CEC levels and pCR rate. Median follow-up was 43 months. CTC detection (≥1 CTC/7.5ml) at baseline was associated with shorter 3-year disease-free survival (39% versus 70% for patients without CTC, P<0.01, HR 2.80) and shorter 3-year overall survival (OS) (P<0.01). In multivariate analysis, independent prognostic parameters for shorter survival were absence of hormonal receptors, no pCR and CTC detection at baseline. CEC level at baseline or variations during treatment had no prognostic value.
In this pooled analysis of two prospective trials in nonmetastatic IBC, detection rate of CTC was 39% with a strong and independent prognostic value for survival. Combination of pCR after neoadjuvant treatment with no CTC detection at baseline isolated a subgroup of IBC with excellent OS (94% 3-year OS), suggesting that CTC count could be part of IBC stratification in prospective trials.
Chemoradiotherapy (CRT) is the standard of care for patients diagnosed with locally advanced cervical cancer (LACC), a human papillomavirus (HPV)-related cancer that relapses in 30%-60% of patients. ...This study aimed to (i) design HPV droplet digital PCR (ddPCR) assays for blood detection (including rare genotypes) and (ii) monitor blood HPV circulating tumor DNA (HPV ctDNA) levels during CRT in patients with LACC.
We analyzed blood and tumor samples from 55 patients with HPV-positive LACC treated by CRT in a retrospective cohort (n = 41) and a prospective cohort (n = 14). HPV-ctDNA detection was carried out by genotype-specific ddPCR.
HPV ctDNA was successfully detected in 69% of patients (n = 38/55) before CRT for LACC, including nine patients with a rare genotype. HPV-ctDNA level was correlated with HPV copy number in the tumor (r = 0.41, P < 0.001). HPV-ctDNA positivity for HPV18 (20%, n = 2/10) was significantly lower than for HPV16 (77%, n = 27/35) or other types (90%, n = 9/10, P = 0.002). HPV-ctDNA detection (positive versus negative) before CRT was associated with tumor stage (P = 0.037) and lymph node status (P = 0.02). Taking into account all samples from the end of CRT and during follow-up in the prospective cohort, positive HPV-ctDNA detection was associated with lower disease-free survival (DFS) (P = 0.048) and overall survival (OS) (P = 0.0013).
This is one of the largest studies to report HPV-ctDNA detection before CRT and showed clearance of HPV ctDNA at the end of treatment in most patients. Residual HPV ctDNA at the end of CRT or during follow-up could help to identify patients more likely to experience subsequent relapse.
•HPV ctDNA can be detected before CRT in patients with LACC (69%).•HPV-ctDNA detection was associated with tumor stage and lymph node status.•A lower detection rate of HPV ctDNA was observed for HPV18 genotype.•Residual ctDNA levels after CRT and during follow-up had a prognostic impact.
Genomic imprinting refers to genes that are epigenetically programmed in the germline to express exclusively or preferentially one allele in a parent-of-origin manner. Expression-based genome-wide ...screening for the identification of imprinted genes has failed to uncover a significant number of new imprinted genes, probably because of the high tissue- and developmental-stage specificity of imprinted gene expression. A very large number of technical and biological artifacts can also lead to the erroneous evidence of imprinted gene expression. In this article, we focus on three common sources of potential confounding effects: (i) random monoallelic expression in monoclonal cell populations, (ii) genetically determined monoallelic expression and (iii) contamination or infiltration of embryonic tissues with maternal material. This last situation specifically applies to genes that occur as maternally expressed in the placenta. Beside the use of reciprocal crosses that are instrumental to confirm the parental specificity of expression, we provide additional methods for the detection and elimination of these situations that can be misinterpreted as cases of imprinted expression.
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