Heterogeneous radiological response to neoadjuvant therapy is associated with poor prognosis after resection of colorectal liver metastases

Abstract

a b s t r a c tIntroduction: Surgery combined with perioperative chemotherapy has become standard of care in patients with resectable colorectal liver metastases. However, poor outcome is expected for a significant subgroup. The clinical implications of inter-metastatic heterogeneity remain largely unknown. In a prospective, population-based series of patients undergoing resection of multiple colorectal liver metastases, the aim was to investigate the prevalence and prognostic impact of heterogeneous response to neoadjuvant chemotherapy. Materials and Methods: Radiological response to treatment was evaluated in a lesion-specific manner in 2e5 metastases per patient. Change of lesion diameter was evaluated and response/progression was classified according to three different size thresholds; 3, 4 and 5 mm. A heterogeneous response was defined as progression and response of different metastases in the same patient. Results: In total, 142 patients with 585 liver metastases were examined with the same radiological method (MRI or CT) before and after neoadjuvant treatment. Heterogeneous response to treatment was seen in 16 patients (11%) using the 3 mm size change threshold, and this group had a 5-year cancerspecific survival of 19% compared to 49% for patients with response in all lesions (p ¼ 0.003). Cut-off values of 4e5 mm were less sensitive for detecting a heterogeneous response, but the survival difference was similar and significant. Conclusion: A subgroup of patients with multiple colorectal liver metastases had heterogeneous radiological response to neoadjuvant chemotherapy and poor prognosis. The evaluation of response pattern is easy to perform, feasible in clinical practice and, if validated, a promising biomarker for treatment decisions.

Radiomics predicts response of individual HER2‐amplified colorectal cancer liver metastases in patients treated with HER2‐targeted therapy

“…In our study, heterogeneous radiological response to a targeted therapy was observed in nine of 38 (24%) patients, more than twice the rate reported in the literature for response to chemotherapy, 5,6 and definitely in contrast to the homogeneous pattern of response recently reported in mismatch repair deficiency CRC patients treated with immunotherapy 28 . Lesion specific response has been previously documented in patients treated for lmCRC with targeted agents 7,29,30 .…”

“…This phase II trial showed clinical benefit from treatment in 70% of patients 3 . Unfortunately, as we and others have shown, patients may exhibit a heterogeneous response, some metastases shrinking while others are progressing 4‐6 . Kessel et al 5 have also shown that heterogeneous response, caused by the onset of new resistant tumor clones in some lesions, is a predictor of poor overall survival 7,8 .…”

“…3 Unfortunately, as we and others have shown, patients may exhibit a heterogeneous response, some metastases shrinking while others are progressing. [4][5][6] Kessel et al 5 have also shown that heterogeneous response, caused by the onset of new resistant tumor clones in some lesions, is a predictor of poor overall survival. 7,8 Differentiating which CRC liver metastases (lmCRC) responds and which lingers and eventually will progress in the same patient could pave the way to truly personalized treatment.…”

High Concordance and Negative Prognostic Impact of RAS/BRAF/PIK3CA Mutations in Multiple Resected Colorectal Liver Metastases

“…We have also demonstrated that intermetastatic heterogeneity in response to neoadjuvant treatment will be associated with poor survival after resection of CRLMs. 47 This response heterogeneity was not explained by the heterogeneity in these driver genes, indicating that several aspects of heterogeneity can be associated with disease behavior and prognosis.…”

Genomic and prognostic heterogeneity among RAS/BRAFV600E/TP53 co‐mutated resectable colorectal liver metastases

“…The clinical impact of such intermetastatic molecular heterogeneity remains poorly defined [22,23,26], although our study suggested that a high degree of heterogeneity of DNA copy number aberrations (CNAs) is associated with a poor prognosis [25]. We have previously also reported differential radiological responses to standard neoadjuvant treatment among metastatic lesions in a subgroup of approximately 10% of patients with resectable CRLM [27]. How this phenotypic heterogeneity relates to molecular heterogeneity is currently not clear, but the poor survival rate of this patient subgroup after surgery highlights the potential clinical importance of intermetastatic heterogeneity.…”