2026年5月15~17日，第十六届浙江大学大肠癌学术论坛在杭州举行。本次大会由浙江大学医学院附属第二医院、浙江省抗癌协会联合主办，《实用肿瘤杂志》协办，以“结直肠癌多学科规范化以及精准化诊治”为主题，聚焦结直肠癌（CRC）临床研究最新动态与学术争议热点，汇聚国内外知名专家，共同探讨CRC诊疗理念与实践路径的持续进阶。

在转移性CRC（mCRC）领域，分子病理检测正以前所未有的速度重塑临床决策逻辑。从RAS、BRAF、MSI、HER2等关键分子标志物，到NGS、液体活检、药物基因组学，再到免疫治疗、靶向治疗、ADC及双特异性抗体等新兴策略，临床治疗正在由“按部就班”的经验模式，逐步转向以分子特征为核心的精准诊疗体系。

本次会议期间，来自南加州大学诺里斯癌症中心Heinz-Josef Lenz教授围绕“mCRC的新兴治疗策略：从分子病理到精准诊疗”进行专题报告，并接受《肿瘤瞭望消化时讯》专访。访谈中，Lenz教授系统阐述了当前mCRC最具临床指导价值的核心分子靶点，分享了复杂分子分型患者的一线及后线治疗布局思路，并进一步展望了dMMR、高微卫星不稳定性（MSI-H）、BRAF突变、KRAS突变这类特殊亚型mCRC的治疗突破。

《肿瘤瞭望消化时讯》

您本次演讲聚焦mCRC从分子病理到精准诊疗的新兴治疗策略。在临床实践中，您认为目前最具指导价值的核心分子靶点有哪些？

Heinz-Josef Lenz教授

我认为，我们正处在一场真正意义上的“分子革命”之中。

对于mCRC患者，制定治疗方案前至少应完成几项核心检测，这至关重要。这些核心检测包括KRAS、NRAS和BRAF突变，MSI及HER2状态。这些分子标志物之所以重要，是因为围绕它们已经形成了相应的一线治疗推荐，能够直接影响治疗路径选择。

对于具有这些分子特征的患者，目前已形成可用于一线及二线治疗的既定治疗策略，这也是为何必须在开始治疗前完成上述检测的原因。

对于mCRC患者而言，最重要的临床决策在于一线治疗阶段即启用最有效的治疗方案，因为随着治疗线数的后移，靶向治疗的疗效往往会随之降低。

Q1：Your presentation focuses on emerging therapeutic strategies for metastatic colorectal cancer, ranging from molecular pathology to precision diagnosis and treatment. In clinical practice, what do you believe are the most clinically valuable core molecular targets at present?

We are living in a molecular revolution.

It has become very important that we should do at least minimum testing which is needed to make treatment decisions for patients with metastatic disease which should include  KRAS and NRAS mutations, BRAF mutation, microsatellite instability, and HER2.

For patients with these molecular characteristics, we already have treatment strategies in the first and secondline setting, which is the reason to complete this testing before starting treatment.

The most important decision for patients with metastatic colon cancer is the initiate the most effective therapy in the first-line as efficacy decreases using targeted therapies in later line of therapy.

《肿瘤瞭望消化时讯》

对于临床中分子病理特征复杂、多靶点共存的mCRC患者，您在制定精准治疗方案时，优先考量的决策依据是什么？

Heinz-Josef Lenz教授

在我们中心，每位新确诊的患者都会接受基于组织和血液的二代测序（NGS）检测。液体活检结果会在一周内出炉，以便选择最有效的治疗方案。

但现实问题是，NGS检测有时需要两到三周才能返回结果。对于mCRC患者，尤其是需要尽快启动治疗的人群而言，这样的等待时间可能过长，甚至可能造成治疗延误。因此，我们通常也会同步进行基于NGS技术的液体活检。液体活检的优势在于结果返回更快，通常一周左右即可获得。

通过NGS检测结果，我们可以了解肿瘤的基因组成，从而制定一线和后续治疗策略。这一点在开展针对特定分子亚组的临床试验时尤为重要，因为它允许我们根据肿瘤的基因突变特征，优先匹配最合适的临床试验。

因此，分子特征不仅对一线治疗决策至关重要，同时也为后线治疗提供了机会和选择，并为患者匹配与其分子特征相符的临床试验提供了依据。

Q2：For patients with metastatic colorectal cancer who present complex molecular pathological features and co-existing multiple targets, what key decision-making factors do you prioritize when formulating precise treatment regimens?

In our center, every newly diagnosed patient receives a next-generation sequencing panel on tissue and on blood. As the liquid biopsy results will become available within 1 week allowing the selection of the most effective therapy. 

The problem is that NGS testing sometimes takes two to three weeks, which is too long if treatment decisions need to be made quickly, and it may delay treatment for this patient population.Therefore, I also perform liquid biopsy using an NGS-based technology, which allows me to receive the results within one week.

With the results of the NGS testing showing the genetic makeup of the tumor, I can develop and plan treatment strategies for first but also for later lines of therapies.

This is particularly important when clinical trials are available for specific molecular defined subgroups, because this will allow us to  prioritize trials based on the genetic makeup of the tumor.

Therefore, the molecular makeup is very critical for first-line treatment, but it also outlines opportunities and options for later lines of treatment, as well as potential clinical trials that may fit the patient’s characteristics.

《肿瘤瞭望消化时讯》

从分子病理诊断落地到临床精准诊疗实践，您认为目前mCRC在临床应用中还存在哪些难点与挑战？未来又有哪些值得期待的发展方向？

Heinz-Josef Lenz教授

我认为分子检测在临床推广过程中面临的最大挑战，通常并不是技术本身，而是检测可及性以及费用支付问题。

在美国，幸运的是患者可以免费获得NGS检测和液体活检。但在全球许多国家和地区，情况并非如此，检测费用所带来的经济负担，可能会限制这些技术在真实临床中的使用、整合和落地，也会影响患者是否能够真正从精准诊疗中获益。

展望未来，基于NGS检测结果的新靶点和新治疗方案将变得至关重要。关键在于，必须确保所有患者都能获得分子检测的机会，尤其是针对CRC独特分子通路的突破性治疗策略。这些新技术通常包括抗体偶联药物（ADC），其在肿瘤中具有非常独特的靶点和肿瘤特异性受体；或者双特异性抗体，其也与特定的癌症特征相关。

在此基础上，这些可靶向的预测性与预后性生物标志物在CRC中的价值将愈发凸显，帮助我们识别出最可能获得高疗效、同时毒性风险最低的人群。分子检测不仅用于治疗方案的选择，还用于潜在的药物剂量调整。药物基因组学在治疗决策中发挥着越来越重要的作用，建议对每位患者进行二氢嘧啶脱氢酶（DPD）和尿苷二磷酸葡糖醛酸转移酶1A1（UGT1A1）基因检测，以避免5-氟尿嘧啶或伊立替康等药物可能引起的危及生命的副作用。

综上所述，分子检测涉及的因素繁多：既包括治疗方案选择和潜在临床试验机会，也包括药物剂量优化和严重毒性反应的预防。

Q3：From the implementation of molecular pathological diagnosis to the clinical practice of precision diagnosis and treatment, what difficulties and challenges do you think still exist in the clinical application of metastatic colorectal cancer? What promising development directions can we expect in the future?

I think the biggest challenge for testing is usually access and who pays for the testing.

In the United States, we are very fortunate that NGS testing and liquid biopsy are free for our patients. But in many countries around the world, that is not the case, and the financial burden can limit the use, integration, and implementation of these tests in clinical care.

Looking ahead, novel targets and novel treatment options will become very important which are based on NGS testing results. It is critical to provide access to molecular testing for all patients particular with emergent treatment strategies targeting unique molecular pathways in colon cancer.  New technologies usually include antibody-drug conjugates, which have very unique targets in tumors and very unique tumor-specific receptors, or bispecific antibodies, which are also linked to very specific cancer characteristics.

In the future, these targetable predictive and prognostic biomarker in colon cancer will become very important to measure, so that we can better select patients who are most likely to achieve the highest efficacy and the least toxicity.

Molecular testing is not only used for treatment selection, but also for potential drug dosing. Pharmacogenomics plays an increased role in treatment decisions, it is recommended to test every patient for DPYD and UGT1A1 to avoid life threatening side effects from 5-FU or irinotecan. . 

So many factors are involved—not only in choosing treatment and identifying potential clinical trials, but also in dosing and preventing significant toxicities.

《肿瘤瞭望消化时讯》

针对dMMR、MSI-H，BRAF突变、KRAS突变这类特殊亚型mCRC，目前有哪些突破性的新兴治疗方案？

Heinz-Josef Lenz教授

对于MSI-H型mCRC，治疗格局已经发生了范式转变。这些患者不再需要接受一线化疗。免疫联合疗法在该人群中实现了极高的客观缓解率，许多患者甚至可获得治愈。

过去，这类患者往往预后很差，生存期通常不超过12个月。如今，得益于免疫治疗，大多数患者能够实现临床治愈，且伴随更低的毒副作用。因此，MSI-H型mCRC无疑是精准治疗改变临床实践的典型代表。目前，在全球范围内，免疫治疗已经成为这类患者的首选治疗方式。

对于其他具有特定分子特征的患者，例如KRAS突变或BRAF突变人群，也取得了重要进展。以BRAF突变为例，BRAF抑制剂已经被整合进治疗策略中，可与西妥昔单抗或帕尼单抗联合，并在一线治疗中与化疗联合应用。对于原本预后较差的患者，这类联合策略已经显示出良好的生存获益。

展望未来，KRAS G12C抑制剂将是一个非常重要的方向。目前，G12C抑制剂在CRC中常与EGFR抑制剂联合使用，并且已经在难治性患者中显示出一定疗效。我认为，未来这类针对G12C的联合治疗策略将进一步前移，进入一线治疗组合。

类似地，针对HER2过表达或HER2扩增肿瘤的新治疗策略，也有望进入一线联合治疗。毫无疑问，这些策略将产生显著影响，并进一步提升疗效。

总体来看，所有这些正在开发和验证中的新分子靶点，未来都有望进入一线联合治疗布局。与此同时，我们也期待ADC带来新的联合治疗可能。ADC本质上是通过特异性受体，将化疗药物更精准地递送至癌细胞。未来，ADC可能会与单克隆抗体、双特异性抗体或抗VEGF治疗联合使用，并很可能率先进入二线治疗场景。

Q4：For special subtypes of metastatic colorectal cancer such as dMMR, MSI-H, BRAF-mutant, and KRAS-mutant tumors, what breakthrough emerging therapeutic strategies are currently available?

For MSI-high disease, there has been a paradigm change.

These patients should no longer receive chemotherapy in the first-line therapy. They have such high response rates to immunotherapy combinations that many of these patients are cured.

These used to be patients with very poor survival, and they usually did not live longer than 12 months. Now, the majority of them can be cured with immunotherapy, with much fewer side effects.

This is certainly paradigm-changing, and immunotherapy has become the treatment of choice worldwide.

For other molecular characteristics, such as KRAS mutations or BRAF mutations, we have already seen that BRAF inhibitors are now integrated in combination with cetuximab or panitumumab, with chemotherapy in the first-line setting, showing incredible survival benefits, again for patients who usually have very poor outcomes.

I think what we are going to see in the future is that G12C inhibitors, which are also combined in colon cancer with EGFR inhibitors and have shown some efficacy in refractory cancer patients, will move into first-line combinations targeting G12C.

Similarly, new approaches targeting HER2-overexpressing or HER2-amplified tumors will also move into first-line combinations. I have no doubt that they will have a dramatic effect and increase efficacy.

All these new molecular targets that are being developed will move into first-line combinations.

Hopefully, we will also see novel treatment combinations with ADCs, which are essentially chemotherapy delivered specifically to cancer cells through specific receptors. These will likely be combined with monoclonal antibodies, bispecific antibodies, or anti-VEGF therapies, and they are likely to move into the second-line setting.

专家简介


Heinz-Josef Lenz

医学博士，南加州大学医学、预防医学及癌症生物学教授
J Terrence Lanni癌症研究讲席教授
南加州大学诺里斯癌症中心副主任和药物开发中心联合主任
全球胃肠道肿瘤学领域的领导者
首次证明基因表达特征(CMS)具有预测和预后价值，现已在全球范围内用于药物开发
首次在随机I期临床试验(80405)中应用下一代测序技术(NGS)，并成功识别出新的药物靶点

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