Even if
wild-type and
-negative metastatic colorectal cancer (mCRC) patients frequently respond to anti-EGFR mAbs, acquired resistance almost invariably occurs. Mechanisms of resistance to EGFR ...blockade include the emergence of
,
, and
extracellular domain mutations as well as
alterations. However, these findings derive from retrospective studies that analyzed one single resistance mechanism at a time; moreover, it is still unclear how molecular heterogeneity affects clonal evolution in patients. In this work, we aimed at extensively characterizing and correlating the molecular characteristics of tissue- and blood-based data in a prospective cohort of patients with mCRC who received anti-EGFR antibodies.
Twenty-two
-
wild-type,
-negative mCRC patients progressing on anti-EGFR therapy after initial response underwent rebiopsy. Next-generation sequencing and silver
hybridization (SISH)/IHC analyses were performed both on archival tumors and postprogression samples. Circulating tumor (ctDNA) molecular profiles were obtained in matched tissue-plasma samples.
mutations and
amplification were the most frequently detected resistance mechanisms in both tissue and blood sample analysis. On the other hand,
and
ectodomain mutations were much rarer. Patients with acquired
amplification showed worse PFS on anti-EGFRs. We detected both intralesion heterogeneity, as suggested by co-occurrence of different resistance mechanisms in the same sample, and interlesion heterogeneity. The combined analysis of tissue and blood (ctDNA) results highlights the complexity of clonal evolution triggered by EGFR blockade.
Our results indicate that it may be extremely challenging to target the complex landscape of molecular heterogeneity associated with emergence of resistance to targeted therapies in patients with mCRC.
.
In patients with metastatic colorectal cancer (mCRC), baseline circulating tumour DNA (ctDNA) variant allele fraction (VAF) might serve as a surrogate of disease burden and should be evaluated in ...comparison with CEA and RECIST-defined sum of target lesions.
In this pre-planned analysis of the VALENTINO trial, we included patients with RAS wild-type mCRC receiving upfront FOLFOX/panitumumab with available baseline liquid biopsy. CtDNA was analysed by means of a 14-gene NGS panel. For each patient, the gene with the highest VAF in ctDNA was selected.
The final cohort included 135 patients. The median VAF was 12.6% (IQR: 2.0-45.2%). Higher VAF was observed in patients with liver metastases and with synchronous metastases presentation. Patients with high VAF had poorer median OS compared to those with low VAF (21.8 vs 36.5 months; HR: 1.82, 95%CI: 1.20-2.76; p = 0.005). VAF outperformed baseline CEA and target lesion diameter in the prognostic stratification and remained significantly correlated with OS (p = 0.003) in a multivariate model. VAF was not significantly correlated with dimensional response and PFS.
CtDNA measured by VAF is prognostic in patients with RAS wild-type mCRC. Response and PFS after an anti-EGFR-based first-line strategy are independent from initial tumour burden.
Background:
Advanced triple-negative breast cancer (aTNBC) has a poor prognosis; thus, there is a need to identify novel biomarkers to guide future research and improve clinical outcomes.
Objectives:
...We tested the prognostic ability of an emerging, complete blood count (CBC)-based inflammatory biomarker, the pan-immune-inflammation value (PIV), in patients with aTNBC treated with first-line, platinum-based chemotherapy.
Design:
This was a retrospective, monocentric, observational study.
Methods:
We included consecutive aTNBC patients treated with platinum-based, first-line chemotherapy at our Institution, and for whom baseline (C1) CBC data were available. We collected CBC data early on-treatment, when available. PIV was calculated as: (neutrophil count × platelet count × monocyte count)/lymphocyte count. Patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (aBC) were included in a control, non-TNBC cohort.
Results:
A total of 78 aTNBC patients were included. When evaluated as a continuous variable, PIV-C1 was associated with worse overall survival (OS; p < 0.001) and progression-free survival (PFS; p < 0.001). On the other hand, when PIV-C1 was assessed on the basis of its quantile distribution, patients with ‘high PIV-C1’ experienced worse OS adjusted hazard ratio (HR): 4.46, 95% confidence interval (CI): 2.22–8.99; adjusted p < 0.001 and PFS (adjusted HR: 2.03, 95% CI: 1.08–3.80; adjusted p = 0.027) when compared to patients with ‘low PIV-C1’. Higher PIV-C1 was also associated with primary resistance to chemotherapy. Similarly, a higher PIV calculated from CBC at C2D1 (PIV-C2) was associated with worse survival outcomes. We also created a PIV-based score combining information about both PIV-C1 and PIV-C2 and allowing the stratification of patients at low, intermediate, and high risk of death. No association was observed between PIV-C1 and clinical outcomes of HR+/HER2− aBC patients.
Conclusion:
PIV has a promising prognostic discrimination ability in aTNBC patients treated with first-line, platinum-based chemotherapy. Both baseline and early on-treatment PIV are associated with clinical outcomes and may be exploited for creating PIV-based risk classifiers if further validated.
Beyond programmed death ligand 1 (PD-L1), no other biomarkers for immunotherapy are used in daily practice. We previously created EPSILoN (Eastern Cooperative Oncology Group performance status (ECOG ...PS), smoking, liver metastases, lactate dehydrogenase (LDH), neutrophil-to-lymphocyte ratio (NLR)) score, a clinical/biochemical prognostic score, in 154 patients treated with second/further-line immunotherapy. This study's aim was to validate EPSILoN score in a different population group.
193 patients were included at National Cancer Institute of Milan (second-line immunotherapy, 61%; further-line immunotherapy, 39%). Clinical/laboratory parameters such as neutrophil-to-lymphocyte ratio and lactate dehydrogenase levels were collected. Kaplan-Meier and Cox hazard methods were used for survival analysis.
Overall median progression-free survival and median overall survival were 2.3 and 7.6 months, respectively. Multivariate analyses for Progression-Free Survival (PFS) identified heavy smokers (hazard ratio (HR) 0.71,
= 0.036) and baseline LDH < 400 mg/dL (HR 0.66,
= 0.026) as independent positive factors and liver metastases (HR 1.48,
= 0.04) and NLR ≥ 4 (HR 1.49,
= 0.029) as negative prognostic factors. These five factors were included in the EPSILoN score which was able to stratify patients in three different prognostic groups, high, intermediate and low, with PFS of 6.0, 3.8 and 1.9 months, respectively (HR 1.94,
< 0.001); high, intermediate and low prognostic groups had overall survival (OS) of 24.5, 8.9 and 3.4 months, respectively (HR 2.40,
< 0.001).
EPSILoN, combining five baseline clinical/blood parameters (ECOG PS, smoking, liver metastases, LDH, NLR), may help to identify advanced non-small-cell lung cancer (aNSCLC) patients who most likely benefit from immune checkpoint inhibitors (ICIs).
Background:
Recently, pro-gastrin-releasing peptide (pro-GRP) became available as an alternative sensitive, specific and reliable tumor marker for patients with small cell lung cancer (SCLC), both in ...limited (LD) and diffuse disease (DD).
Methods:
We retrospectively analyzed pro-GRP, neuron-specific enolase (NSE) and CEA in patients with SCLC and non-small cell lung cancer (NSCLC). Serum pro-GRP level was measured with electrochemiluminescence at our laboratory (cutoff 77.8 pg/mL). Continuous variables were analyzed with the Mann-Whitney test, contingency data with Fisher’s exact test. Receiver operator characteristic (ROC) curve analysis was performed to identify threshold values to set the highest sensitivity (Sn) and specificity (Sp) values.
Results:
A total of 65 patients were studied (49 men, median age 67 years, range 27-79). Thirty-seven patients had SCLC (29 DD, 8 LD) and 28 advanced NSCLC. Median pro-GRP level was 919 pg/mL (range 22-147,350) in SCLC and 32 pg/mL (range 10-119.2) in NSCLC (p<0.0001). NSE was 4.38-fold higher in SCLC patients (p = 0.0005); CEA did not reveal significant differences between groups. Pro-GRP Sn and Sp were 86.4% and 96.4%, respectively. With ROC curve analysis, a cutoff value of 329.3 pg/mL showed a Sn of 75.8% and Sp of 87.5% in discriminating DD from LD. Pro-GRP was not influenced by either liver metastases or renal impairment.
Conclusions:
Pro-GRP is sensitive for SCLC diagnosis. Since high marker levels are related to high disease burden, pro-GRP may have a negative prognostic significance. Follow-up studies are required to define its role in clinical practice in monitoring responses to treatment and early relapses.
Biliary tract cancers (BTCs) are rare and lethal cancers, with a 5-year survival inferior to 20%(1-3). The only potential curative treatment is surgical resection. However, despite complex surgical ...procedures that have a remarkable risk of postoperative morbidity and mortality, the 5-year survival rate after radical surgery (R0) is 20-40% and recurrence rates are up to ~ 75%(4-6). Up to ~ 40% of patients relapse within 12 months after resection, and half of these patient will recur systemically(4-6). There is no standard of care for neoadjuvant chemotherapy (NAC) in resectable BTC, but retrospective reports suggest its potential benefit (7, 8).
PURITY is a no-profit, multicentre, randomized phase II/III trial aimed at evaluating the efficacy of the combination of gemcitabine, cisplatin and nabpaclitaxel (GAP) as neoadjuvant treatment in patients with resectable BTC at high risk for recurrence. Primary objective of this study is to evaluate the efficacy of neoadjuvant GAP followed by surgery as compared to upfront surgery, in terms of 12-month progression-free survival for the phase II part and of progression free survival (PFS) for the phase III study. Key Secondary objectives are event free survival (EFS), relapse-free survival, (RFS), overall survival (OS), R0/R1/R2 resection rate, quality of life (QoL), overall response rate (ORR), resectability. Safety analyses will include toxicity rate and perioperative morbidity and mortality rate. Exploratory studies including Next-Generation Sequencing (NGS) in archival tumor tissues and longitudinal ctDNA analysis are planned to identify potential biomarkers of primary resistance and prognosis.
Considering the poor prognosis of resected BTC experiencing early tumor recurrence and the negative prognostic impact of R1/R2 resections, PURITY study is based on the rationale that NAC may improve R0 resection rates and ultimately patients' outcomes. Furthermore, NAC should allow early eradication of microscopic distant metastases, undetectable by imaging but already present at the time of diagnosis and avoid mortality and morbidity associated with resection for patients with rapid progression or worsening general condition during neoadjuvant therapy. The randomized PURITY study will evaluate whether patients affected by BTC at high risk from recurrence benefit from a neoadjuvant therapy with GAP regimen as compared to immediate surgery.
PURITY is registered at ClinicalTrials.gov (NCT06037980) and EuCT(2023-503295-25-00).
Abstract
Background
Despite the increasing number of treatment options, reliable prognostic/predictive biomarkers are still missing for patients affected by metastatic clear cell renal cell carcinoma ...(mccRCC).
Methods
Patients with mccRCC undergoing standard first line treatment were enrolled. Blood (12 ml) was drawn at treatment baseline and circulating free DNA (cfDNA) was extracted from plasma. Next-generation sequencing (NGS) was performed on cfDNA using the Oncomine Pan-Cancer Cell-Free Assay and clinical outcomes were correlated with liquid biopsy findings.
Results
A total of 48 patients were enrolled, 12 received immunotherapy and 36 received a vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI). A cfDNA cut-off of 0.883 ng/μl stratified patients based on progression-free survival (PFS) and overall survival (OS) (p = 0.001 and p = 0.008, respectively). cfDNA amount was also correlated with best response (p = 0.006). Additional cfDNA cut-points divided patients into short, intermediate and long responders, with PFS of 4.87 vs 9.13 vs 23.1 months, respectively (p < 0.001). PFS resulted to be significantly shorter in carriers of mutant TP53 compared to not carriers (p = 0.04). Patients with high cfDNA levels and mutant TP53 have the worst PFS, while patients with low cfDNA amounts and no mutations in TP53 displayed the longest PFS (p = 0.004).
Conclusions
The present study demonstrates that cfDNA and TP53 are potential predictive biomarkers of response in mccRCC to be further explored in larger and/or prospective studies.
The clinical relevance of circulating tumor cell clusters (CTC-clusters) in breast cancer (BC) has been mostly studied using the CellSearch®, a marker-dependent method detecting only ...epithelial-enriched clusters. However, due to epithelial-to-mesenchymal transition, resorting to marker-independent approaches can improve CTC-cluster detection. Blood samples collected from healthy donors and spiked-in with tumor mammospheres, or from BC patients, were processed for CTC-cluster detection with 3 technologies: CellSearch®, CellSieve™ filters, and ScreenCell® filters. In spiked-in samples, the 3 technologies showed similar recovery capability, whereas, in 19 clinical samples processed in parallel with CellSearch® and CellSieve™ filters, filtration allowed us to detect more CTC-clusters than CellSearch® (median number = 7 versus 1, p = 0.0038). Next, samples from 37 early BC (EBC) and 23 metastatic BC (MBC) patients were processed using ScreenCell® filters for attaining both unbiased enrichment and marker-independent identification (based on cytomorphological criteria). At baseline, CTC-clusters were detected in 70% of EBC cases and in 20% of MBC patients (median number = 2, range 0–20, versus 0, range 0–15, p = 0.0015). Marker-independent approaches for CTC-cluster assessment improve detection and show that CTC-clusters are more frequent in EBC than in MBC patients, a novel finding suggesting that dissemination of CTC-clusters is an early event in BC natural history.
Combined MET and BRAF inhibition showed clinical benefit in a patient with rectal cancer carrying BRAF
and MET amplification. However after 4 months, acquired resistance emerged and the patient ...deceased shortly after disease progression. The mechanism of resistance to this drug combination is unknown.
We analysed plasma circulating tumour DNA obtained at progression by exome sequencing and digital PCR. MET gene and mRNA in situ hybridisation analyses in two bioptic specimens obtained at progression were used to confirm the plasma data.
We identified in plasma MET gene hyper-amplification as a potential mechanism underlying therapy resistance. Increased MET gene copy and transcript levels were detected in liver and lymph node metastatic biopsies. Finally, transduction of MET in BRAF mutant colorectal cancer cells conferred refractoriness to BRAF and MET inhibition.
We identified in a rectal cancer patient MET gene hyper-amplification as mechanism of resistance to dual BRAF and MET inhibition.
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