Treatment of young adults with colorectal cancer (CRC) represents an unmet clinical need, especially as diagnosis in this population might lead to the greatest loss of years of life. Since 1994, CRC ...incidence in individuals younger than 50 years has been increasing by 2% per year. The surge in CRC incidence in young adults is particularly alarming as the overall CRC frequency has been decreasing. Early‐onset CRC are characterized by a more advanced stage at diagnosis, poorer cell differentiation, higher prevalence of signet ring cell histology, and left colon‐sided location of the primary tumor. Among EO‐CRC, approximately 30% of patients are affected by tumors harboring mutations causing hereditary cancer predisposing syndromes, and 20% have familial CRC. Most notably, the remaining 50% of EO‐CRC patients have neither hereditary syndromes nor familial CRC, thus representing a formidable challenge for research. In this review article we summarize epidemiology, clinical and molecular features, heredity and outcome of treatments of EO‐CRC, and provide considerations for future perspectives.
The prevalence of hereditary syndromes, familial syndromes and neither hereditary or familial (‘terra incognita’) syndromes among early‐onset colorectal cancer in young individuals. Figures are derived from studies in the text.
Entrectinib is a first-in-class pan-TRK kinase inhibitor currently undergoing clinical testing in colorectal cancer and other tumor types. A patient with metastatic colorectal cancer harboring an ...LMNA-NTRK1 rearrangement displayed a remarkable response to treatment with entrectinib, which was followed by the emergence of resistance. To characterize the molecular bases of the patient's relapse, circulating tumor DNA (ctDNA) was collected longitudinally during treatment, and a tissue biopsy, obtained before entrectinib treatment, was transplanted in mice (xenopatient), which then received the same entrectinib regimen until resistance developed. Genetic profiling of ctDNA and xenopatient samples showed acquisition of two point mutations in the catalytic domain of NTRK1, p.G595R and p.G667C. Biochemical and pharmacologic analysis in multiple preclinical models confirmed that either mutation renders the TRKA kinase insensitive to entrectinib. These findings can be immediately exploited to design next-generation TRKA inhibitors.
We provide proof of principle that analyses of xenopatients (avatar) and liquid biopsies allow the identification of drug resistance mechanisms in parallel with clinical treatment of an individual patient. We describe for the first time that p.G595R and p.G667C TRKA mutations drive acquired resistance to entrectinib in colorectal cancers carrying NTRK1 rearrangements.
Summary Background We previously found that dual HER2 blockade with trastuzumab and lapatinib led to inhibition of tumour growth in patient-derived xenografts of HER2 -amplified metastatic colorectal ...cancer. In this study, we aimed to assess the antitumour activity of trastuzumab and lapatinib in patients with HER2-positive colorectal cancer. Methods HERACLES was a proof-of-concept, multicentre, open-label, phase 2 trial done at four Italian academic cancer centres. We enrolled adult patients with KRAS exon 2 (codons 12 and 13) wild-type and HER2-positive metastatic colorectal cancer refractory to standard of care (including cetuximab or panitumumab), an Eastern Cooperative Oncology Group performance status of 0 or 1, and at least one measurable lesion. We defined HER2 positivity in tumour samples by use of immunohistochemistry and fluorescence in-situ hybridisation in accordance with our previously validated colorectal cancer-specific diagnostic criteria. Eligible patients received intravenous trastuzumab at 4 mg/kg loading dose followed by 2 mg/kg once per week, and oral lapatinib at 1000 mg per day until evidence of disease progression. The primary endpoint was the proportion of patients achieving an objective response (defined as complete response or partial response), which was assessed by independent central review in the intention-to-treat population. This trial is registered with EudraCT, number 2012-002128-33. Findings Between Aug 27, 2012, and May 15, 2015, we screened 914 patients with KRAS exon 2 (codons 12 and 13) wild-type metastatic colorectal cancer and identified 48 (5%) patients with HER2-positive tumours, although two died before enrolment. Of these patients, 27 were eligible for the trial. All were evaluable for response. At the time of data cutoff on Oct 15, 2015, with a median follow-up of 94 weeks (IQR 51–127), eight (30%, 95% CI 14–50) of 27 patients had achieved an objective response, with one patient (4%, 95% CI −3 to 11) achieving a complete response, and seven (26%, 95% CI 9–43) achieving partial responses; 12 (44%, 95% CI 25–63) patients had stable disease. Six (22%) of 27 patients had grade 3 adverse events, which consisted of fatigue in four patients, skin rash in one patient, and increased bilirubin concentration in one patient. No grade 4 or 5 adverse events were reported. We detected no drug-related serious adverse events. Interpretation The combination of trastuzumab and lapatinib is active and well tolerated in treatment-refractory patients with HER2-positive metastatic colorectal cancer. Funding Associazione Italiana Ricerca Cancro (AIRC), Fondazione Oncologia Niguarda Onlus, and Roche.
The aim of our study was to develop and validate a machine learning algorithm to predict response of individual HER2‐amplified colorectal cancer liver metastases (lmCRC) undergoing dual HER2‐targeted ...therapy. Twenty‐four radiomics features were extracted after 3D manual segmentation of 141 lmCRC on pretreatment portal CT scans of a cohort including 38 HER2‐amplified patients; feature selection was then performed using genetic algorithms. lmCRC were classified as nonresponders (R−), if their largest diameter increased more than 10% at a CT scan performed after 3 months of treatment, responders (R+) otherwise. Sensitivity, specificity, negative (NPV) and positive (PPV) predictive values in correctly classifying individual lesion and overall patient response were assessed on a training dataset and then validated on a second dataset using a Gaussian naïve Bayesian classifier. Per‐lesion sensitivity, specificity, NPV and PPV were 89%, 85%, 93%, 78% and 90%, 42%, 73%, 71% respectively in the testing and validation datasets. Per‐patient sensitivity and specificity were 92% and 86%. Heterogeneous response was observed in 9 of 38 patients (24%). Five of nine patients were carriers of nonresponder lesions correctly classified as such by our radiomics signature, including four of seven harboring only one nonresponder lesion. The developed method has been proven effective in predicting behavior of individual metastases to targeted treatment in a cohort of HER2 amplified patients. The model accurately detects responder lesions and identifies nonresponder lesions in patients with heterogeneous response, potentially paving the way to multimodal treatment in selected patients. Further validation will be needed to confirm our findings.
What's new?
Therapies targeting human epidermal growth factor receptor 2 (HER2) have shown promise in patients with metastatic colorectal cancer (CRC) with HER2 amplification. Predicting which CRC metastases respond to HER2‐targeted therapy could significantly advance personalized treatment in this patient subpopulation. Here, employing a machine learning method, the authors describe a novel radiomics signature capable of predicting liver metastasis response to HER2‐targeted therapy. The model correctly identified non‐responder lesions in patients with heterogeneous therapeutic response. The ability of the radiomics signature to identify HER2 therapy‐responsive liver metastases could facilitate the generation of more sophisticated diagnostic and therapeutic strategies in select CRC patients.
Immune checkpoint inhibitors (CPIs) represent an effective therapeutic strategy for several different types of solid tumors and are remarkably effective in mismatch repair deficient (MMRd) tumors, ...including colorectal cancer (CRC). The prevalent view is that the elevated and dynamic neoantigen burden associated with the mutator phenotype of MMRd fosters enhanced immune surveillance of these cancers. In addition, recent findings suggest that MMRd tumors have increased cytosolic DNA, which triggers the cGAS STING pathway, leading to interferon-mediated immune response. Unfortunately, approximately 30% of MMRd CRC exhibit primary resistance to CPIs, while a substantial fraction of tumors acquires resistance after an initial benefit. Profiling of clinical samples and preclinical studies suggests that alterations in the Wnt and the JAK-STAT signaling pathways are associated with refractoriness to CPIs. Intriguingly, mutations in the antigen presentation machinery, such as loss of MHC or Beta-2 microglobulin (B2M), are implicated in initial immune evasion but do not impair response to CPIs. In this review, we outline how understanding the mechanistic basis of immune evasion and CPI resistance in MMRd CRC provides the rationale for innovative strategies to increase the subset of patients benefiting from CPIs.
The EGFR-targeted antibodies cetuximab and panitumumab are used to treat metastatic colorectal cancers. Mutations in KRAS, NRAS, and BRAF and amplification of ERBB2 and MET drive primary (de novo) ...resistance to anti-EGFR treatment. Recently, the emergence of alterations in the same genes was detected in patients who responded to EGFR blockade and then relapsed. These results illuminate a striking overlap between genes that, when mutated, drive primary and secondary resistance to anti-EGFR antibodies. Remarkably, although the mechanisms of resistance are genetically heterogeneous, they biochemically converge on key signaling pathways. This knowledge is being translated in the rational design of additional lines of therapy.
Anti-EGFR-targeted therapies are used for the treatment of metastatic colorectal cancer. Molecular heterogeneity impairs their efficacy by fuelling de novo and acquired resistance. In this review, we highlight how genetically distinct resistance mechanisms biochemically converge on a limited number of signaling pathways that can be therapeutically intercepted.
Anti‐EGFRs plus doublet chemotherapy is considered the optimal upfront option for RAS/BRAF wild‐type left‐sided metastatic colorectal cancer (mCRC). Early‐onset (EO) mCRC has an increasing incidence ...and its prognostic/predictive role and management is debatable. We performed a post hoc analysis of Valentino study, that randomized RAS wild‐type mCRC patients to two panitumumab‐based maintenance regimens after FOLFOX/panitumumab induction. We assessed the safety and efficacy outcomes in patients stratified for age (<50/≥50 years old). We assessed progression‐free survival (PFS), overall survival (OS), response rate (ORR), rate of treatment‐related and panitumumab‐related adverse events (AEs) and quality of life (QoL). In 229 patients enrolled, 35 (15%) had EO mCRC, with a higher rate of female sex (P = .020) and lower rate of primary tumor resection (P = .001). Median PFS and OS were 10.9 vs 10.8 months (P = .593) and 28.1 vs 27.5 months (P = .865) in patients <50 and ≥50 years old, respectively, with no significant impact of maintenance arm. ORR and disease control rate were 74% vs 65% (P = .337) and 97% vs 81% (P = .013) in patients <50 or ≥50 years old. In younger patients, a trend for increased chemotherapy‐related AEs (peculiarly anemia) was shown, while significantly decreased EGFR‐related hypomagnesemia and increased skin rash were reported. No significant differences in treatment intensity or QoL were observed. In patients with EO mCRC and RAS wild‐type status, we found no differences in terms of survival outcomes based on age when selecting maintenance strategies. Management of treatment‐related AEs should consider the differential toxicity profile of age and sex.
What's new?
In patients with RAS and BRAF wild‐type metastatic colorectal cancer (mCRC), doublet chemotherapy with antiepidermal growth factor receptor (anti‐EGFR) agents is a recommended upfront regimen. However, data on the influence of younger age on the efficacy and safety outcomes of an EGFR‐based first‐line treatment strategy remain scant. In this post hoc analysis of the Valentino study, the authors report no significant differences in survival outcomes between patients <50 and ≥50 years old but reveal a differential toxicity profile. Rather than an intensification/modulation of the therapeutic schedule, the results support a differential toxicity management/prevention approach according to age and sex.
Background
HER2 amplification is detected in 3% of patients with colorectal cancer (CRC), making tumors in the metastatic setting vulnerable to double pharmacological HER2 blockade. Preclinical ...findings show that it also might impair response to anti‐epidermal growth factor receptor (EGFR) treatment.
Subjects and Methods
Patients with KRAS exon 2 wild‐type metastatic CRC underwent molecular screening of HER2 positivity by HERACLES criteria (immunohistochemistry 3+ or 2+ in ≥50% of cells, confirmed by fluorescence in situ hybridization). A sample of consecutive HER2‐negative patients was selected as control. A regression modeling strategy was applied to identify predictors explaining the bulk of HER2 positivity and the association with response to previous anti‐EGFR treatment.
Results
From August 2012 to April 2018, a total of 100 HER2‐positive metastatic CRC tumors were detected out of 1,485 KRAS exon 2 wild‐type screened patients (6.7%). HER2‐positive patients show more frequently lung metastases (odds ratio OR, 2.04; 95% confidence interval CI, 1.15–3.61; p = .014) and higher tumor burden (OR, 1.48; 95% CI, 1.10–2.01; p = .011), and tumors were more likely to be left sided (OR, 0.50; 95% CI, 0.22–1.11; p = .088). HER2‐positive patients who received treatment with anti‐EGFR agents (n = 79) showed poorer outcome (objective response rate, 31.2% vs. 46.9%, p = .031; progression‐free survival, 5.7 months vs. 7 months, p = .087).
Conclusion
Testing for HER2 should be offered to all patients with metastatic CRC because the occurrence of this biomarker is unlikely to be predicted based on main clinicopathological features. Patients with HER2‐amplified metastatic CRC are less likely to respond to anti‐EGFR therapy.
Implications for Practice
Patients with HER2‐amplified/overexpressed metastatic colorectal cancer (mCRC) harbor a driver actionable molecular alteration that has been shown in preclinical models to hamper efficacy of the anti‐epidermal growth factor receptor (EGFR) targeted therapies. The present study confirmed that this molecular feature was associated with worse objective tumor response and shorter progression‐free survival in response to previous anti‐EGFR therapies. Moreover, it was found that the occurrence of this biomarker is unlikely to be predicted based on main clinicopathological features. Therefore, HER2 status assessment should be included in the molecular diagnostic workup of all mCRC for speedy referral to clinical trials encompassing HER2‐targeted double blockade independently of previous anti‐EGFR treatment.
摘要
背景 3% 的结直肠癌 (CRC) 患者中检测到 HER2 扩增，这使得转移灶中的肿瘤容易受到双重药物 HER2 阻断。临床前研究表明，HER2 还可能损害对抗表皮生长因子受体 (EGFR) 治疗的反应。
受试者和方法 KRAS 外显子 2 野生型转移性CRC患者采用 HERACLES 标准进行 HER2 阳性分子筛查(在 ≥ 50% 的细胞中免疫组化 3 + 或 2+，经荧光原位杂交证实)。选择连续HER2 阴性患者作为对照。采用回归建模策略确定预测因素，对主要 HER2 阳性以及与先前抗 EGFR 治疗反应的相关性进行解析。
结果 2012 年 8 月至 2018 年 4 月期间，在 1 485 例 KRAS 外显子 2 野生型筛查患者中，共检测出 100 例 (6.7%) 转移性 CRC 肿瘤 HER2 阳性患者。HER2 阳性患者肺转移更频繁 比值比 (OR), 2.04; 95% 可信区间 (CI), 1.15‐3.61; p = 0.014，肿瘤负荷较高(OR, 1.48; 95% CI, 1.10‐2.01;p = 0.011)，肿瘤位于左侧的可能性更高(OR, 0.50; 95% CI，0.22‐1.11; p = 0.088)。接受抗 EGFR 药物治疗的 HER2 阳性患者 (n = 79) 预后较差(客观有效率 31.2% vs. 46.9%， p = 0.031；无进展生存期，5.7 个月 vs. 7 个月，p = 0.087)。
结论 HER2 这种生物标志物的发生不太可能根据主要的临床病理特征进行预测，故而所有转移性 CRC 患者均应接受 HER2 检测。HER 2 扩增转移性CRC 患者对抗 EGFR 治疗不太容易产生反应。
实践意义:HER2 扩增/过表达转移性结直肠癌 (mCRC) 患者存在一种驱动可操作的分子改变，临床前模型中显示出，这种改变会阻碍抗表皮生长因子受体 (EGFR) 靶向治疗的疗效。本研究证实，这一分子特征与客观肿瘤反应较差和针对之前的抗 EGFR 治疗的无进展生存时间较短有关。此外，我们还发现这种生物标志物的发生不太可能根据主要的临床病理特征进行预测。因此，所有 mCRC 的分子诊断工作都应纳入 HER2 状态评估，以便在不依赖以往抗 EGFR 治疗的情况下，快速转介到包含 HER2 靶向双重阻断的临床试验中。
This article reports results of a study that examined the clinicopathological characteristics of patients with metastatic colorectal cancer displaying amplification or overexpression of the HER2 oncogene, focusing on response to anti‐EGFR treatment.
The emergence of drug resistance limits the efficacy of targeted therapies in human tumors. The prevalent view is that resistance is a fait accompli: when treatment is initiated, cancers already ...contain drug-resistant mutant cells. Bacteria exposed to antibiotics transiently increase their mutation rates (adaptive mutability), thus improving the likelihood of survival. We investigated whether human colorectal cancer (CRC) cells likewise exploit adaptive mutability to evade therapeutic pressure. We found that epidermal growth factor receptor (EGFR)/BRAF inhibition down-regulates mismatch repair (MMR) and homologous recombination DNA-repair genes and concomitantly up-regulates error-prone polymerases in drug-tolerant (persister) cells. MMR proteins were also down-regulated in patient-derived xenografts and tumor specimens during therapy. EGFR/BRAF inhibition induced DNA damage, increased mutability, and triggered microsatellite instability. Thus, like unicellular organisms, tumor cells evade therapeutic pressures by enhancing mutability.
KRAS mutations are the most common oncogenic event in colorectal cancer (CRC) progression and their occurrence is associated with lack of response to anti epidermal growth factor receptor (EGFR) ...targeted therapies. Using preclinical models and patients' samples we recently reported that the emergence of KRAS mutations but also KRAS amplification is associated with acquired resistance to the EGFR inhibitors cetuximab or panitumumab. We reasoned that KRAS amplification may also be responsible for primary resistance to these agents. Furthermore, while the prevalence of KRAS mutations has been well established in CRC, little is known about the frequency of KRAS amplification in large CRC series. We performed a screening of 1,039 CRC samples to assess the prevalence of KRAS amplification in this tumor type and further evaluated the role of this genetic alteration on the sensitivity to anti EGFR therapies. We detected KRAS amplification in 7/1,039 (0.67%) and 1/102 evaluable CRC specimens and cell lines, respectively. KRAS amplification was mutually exclusive with KRAS mutations. Tumors or cell lines harboring this genetic lesion are not responsive to anti‐EGFR inhibitors. Although KRAS amplification is an infrequent event in CRC, it might be responsible for precluding response to anti‐EGFR treatment in a small proportion of patients.
What's new?
Monoclonal antibodies targeting the Epidermal Growth Factor Receptor (EGFR) are one of the therapeutic options for metastatic colorectal cancer, but they are effective only in a small subset of patients. Here the authors determined the prevalence of KRAS gene amplification in a large dataset of colorectal cancer samples and assessed the possible predictive role of KRAS gene copy number status in response to anti‐EGFR treatment. The data show that amplification of the KRAS oncogene occurs in a small fraction of KRAS wild‐type cases and that KRAS amplification is causally associated with resistance to anti‐EGFR treatment.
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