Ask the big coffee, life is far-reaching| Professor Chen Gong: Precision and precision, explore the road to colorectal cancer treatment optimization

With the innovation and development of medical technology, new drugs/new therapies in the field of colorectal cancer have "bloomed", especially targeted therapy and immunotherapy, setting off a new round of "medical revolution"
in colorectal cancer treatment.
At the just-concluded 2022 European Society for Medical Oncology (ESMO), a number of colorectal cancer research results shined internationally and attracted widespread attention
from the academic community.
In this regard, Yimaitong specially invited Professor Chen Gong of the Cancer Prevention and Treatment Center of Sun Yat-sen University to comment on the important new progress
in the field of colorectal cancer.

Expert profiles

Professor Chen Gong

• Sun Yat-sen University Cancer Center

• Chief physician, doctoral supervisor, deputy director of colorectal department

• Deputy Secretary General of the Chinese Society of Clinical Oncology (CSCO).
  

• Executive Director, Deputy Secretary General of the Asian Alliance of Clinical Oncology (FACO).
  

• Member of the Academic Committee of the American Society of Clinical Oncology (ASCO) from 2015 to 2017.
  

• Chairman of the colorectal cancer special committee of Guangdong Anti-Cancer Association

• 2019 3rd "National Famous Doctor.
  Excellent Style" winner

• Member of the Colorectal Cancer Professional Committee of the Chinese Anti-Cancer Association

• Member of the Standing Committee of the CSCO Colorectal Cancer Committee

• Secretary and author of the CSCO Colorectal Cancer Guidelines Expert Group

• Member of the CSCO National Expert Committee on Gastrointestinal Stromal Tumors

• Member of the Expert Committee on Gastrointestinal and Pancreatic Neuroendocrine Tumors

• Standing Committee Member of Colorectal Surgeon Branch of Chinese Medical Doctor Association

• Vice Chairman of the Oncology MDT Special Committee of China Research Hospital Association

• Vice Chairman of the International Hepatobiliary and Pancreatic Association Metastatic Liver Cancer Committee

• Vice Chairman of Liver Metastasis Branch of Colorectal Cancer Committee of Chinese Medical Doctor Association

• Member of the American Society of Clinical Oncology (ASCO).
  

• Member of the Standing Committee of Guangdong Colorectal Cancer Professional Committee

• Member of the European Society of Oncology (ESMO).
  

Moving forward in exploration: adjuvant intraperitoneal hyperthermic chemotherapy (HIPEC) improves treatment outcomes for locally advanced colon cancer

Professor Chen Gong

Sun Yat-sen University Cancer Center

Locally advanced colon cancer (stage T4, pT4) is considered a high-risk state that can progress to metachronous peritoneal cancer
.
Professor Chen introduced that since most patients with peritoneal metastasis of colorectal cancer have a very poor prognosis, it is important
to screen high-risk patients and intervene early, reduce the occurrence of peritoneal metastasis, select drugs sensitive to peritoneal metastasis, explore comprehensive treatment models, and improve the treatment effect of peritoneal metastasis of colorectal cancer.

Data show that about 25% of pT4 colon cancer patients develop peritoneal metastasis within 3 years after surgical resection, so the prevention and treatment of pT4 colon cancer has gradually been paid attention ^to1,2
.
Studies have found that HIPEC has a unique effect
on the prevention and treatment of peritoneal implantation metastasis of malignant tumors.
In 2019, Dutch scholars tried oxaliplatin-assisted HIPEC treatment in T4 patients through the COLOPEC study
.
Although the results of the COLOPEC study were negative, many scholars have been exploring the therapeutic implications of HIPEC for colorectal cancer patients in recent ^years1
.
The results of a randomized phase III study of
HIPEC adjuvant therapy for locally advanced colon cancer, HIPECT4, were reported at this year's ESMO meeting.
In this study, patients with a preoperative diagnosis of primary locally advanced colon cancer (cT4NxM0) were randomized (1:1) to surgery or surgery plus HIPEC (mitomycin C 30 mg/m², 60 minutes), followed by systemic adjuvant chemotherapy
.
It was found that the addition of mitomycin C intraperitoneal hyperthermic chemotherapy to complete surgical resection improved local control compared with surgery alone
.
This benefit was more pronounced in the pT4 colon cancer ^subgroup2
.
Therefore, the HIPECT4 study has great clinical significance
.

Fig.
1 Results of HIPECT4 studies (overall local control rate versus pT4 subgroup)

Professor Chen pointed out that the HIPECT4 study can obtain completely different results from the 2019 COLOPEC study, and an important reason is that the drug used in the COLOPEC study is a large dose of oxaliplatin for 30 minutes, due to the abdominal irritation and other adverse reactions of the drug, the HIPEC administration time is relatively short, which affects the treatment efficacy
。 The HIPECT4 study used mitomycin C, which is usually toxic, and its good tolerability allows patients to complete adjuvant HIPEC therapy one week after complete surgical resection
.
In addition, HIPEC should be started as soon as possible after primary tumor resection and completed within 1 week as much as possible, while COLOPEC study should be treated with HIPEC 5~8 weeks after surgery, which may not be reasonable
in time.

Breaking the curse of "incurable", KRAS targets have made new progress

Professor Chen Gong

Sun Yat-sen University Cancer Center

Professor Chen introduced that the KRAS gene is the first gene
to achieve precise treatment of colorectal cancer.
In colorectal cancer, the mutation rate of KRAS accounts for about 45%, most of which are KRAS G12D, G12V, G13D mutations, and KRAS G12C mutations account for about 3% of the overall colorectal cancer patients
.
Studies have found that KRAS gene mutations are significantly related to tumor recurrence and metastasis, but patients with KRAS gene mutations have poor efficacy and easy resistance to EGFR antibody cetuximab combined or monotherapy
.
Domestic and foreign colorectal cancer guidelines propose that EGFR inhibitor treatment is recommended only for patients with wild type of KRAS gene
.
Although this target is fatal for tumor patients, due to its large molecule, relatively smooth surface, and strong affinity of KRAS for nucleotide GTP, it is difficult for drugs to compete with GTP, it is difficult to bind KRAS protein and inhibit its activity, since the discovery of KRAS for decades, there has been no targeted targeted drug successfully marketed in the world, so KRAS is known as the "notorious" "undruggable" ^target3,4
。

Figure 2 Mechanism of KRAS pathway

In recent years, with the deepening of more and more research, KRAS G12C inhibitors have emerged
.
At this year's ESMO conference, a number of studies on KRAS in colorectal cancer (such as adagrasib + cetuximab, sotorasib + panitumab) further expanded treatment options
for patients with advanced KRAS G12C mutations with poor prognosis 。 Among them, the KRYSTAL-1 study evaluated the efficacy and safety of Adagrasib in patients with advanced solid tumors with KRAS G12C mutation, and the colorectal cancer cohort included Adagrasib monotherapy and Adagrasib in combination with cetuximab in patients with previously treated colorectal cancer
.
The results showed that the objective response rate (ORR) of Adagrasib monotherapy group was 19%; The ORR of Adagrasib plus cetuximab reached 46%.

The efficacy of another Sotorasib + panitumab in patients with refractory KRAS G12C mutant mCRC is equally encouraging5,6
.
Although the sample size of KRAS G12C mutation-related colorectal cancer studies is relatively limited, these results still give patients hope for life and look forward to the disclosure
of more data in the future.

Rational layout and optimized sequential: FRESCO-2 research is expected to rewrite the pattern of colorectal cancer backline treatment

Professor Chen Gong

Sun Yat-sen University Cancer Center

Professor Chen introduced that at the 2022 ESMO Conference, the "international version" of FRESCO-2 research has attracted the attention
of the academic community.
The study included patients from more countries such as the United States, Europe, and Japan, and the population was richer and more diverse
.
This study not only validates the efficacy and safety of fruquintinib in the fourth and subsequent lines after receiving regorafenib and/or TAS-102, but also analyzes whether front-line medications of interest to clinicians affect the efficacy of fruquintinib7
.

In the FRESCO-2 study, the included patients had previously received regorafenib and/or TAS-102, and 48% of those patients had received regorafenib
in the frontline 。 The data showed that fruquintinib for the fourth-line treatment of regorafenib and/or TAS-102 treated advanced colorectal cancer had a median OS of 7.
4 months, significantly longer than the placebo group for 2.
6 months; the median PFS was 3.
7 months, significantly longer than that of the placebo group by 1.
9 months, and both OS and PFS achieved a statistically significant and clinically significant extension, indicating that fruquintinib may have strong antitumor activity
。 Subgroup data suggest that prior treatment with regorafenib followed by fruquintinib does not affect the efficacy of fruquintinib, reducing the risk of death and disease progression, and increasing the survival ^benefit7
.
This means that the longer the treatment line, the longer
the patient survival.

Fig.
3 Survival outcomes of front-line regorafenib-treated versus fruquintinib in patients without regorafenib

Professor Chen pointed out that there are many drugs that can be used for the treatment of colorectal cancer, and how to line up is a problem
worth considering.
In particular, third-line therapy needs to play a key role
in the whole process of managing metastatic colorectal cancer.
Regarding how to personalize the choice of third-line treatment of mCRC, Professor Chen shared his views: if there is a clear therapeutic target, such as MSI-H, immunotherapy is usually preferred; BRAF mutations, HER2 amplification, etc.
often prioritize precise personalized treatment
for patients.
For the current standard third-line treatment layout, clinicians will consider not only toxicity, drug accessibility, medical insurance, follow-up treatment, etc.
, but also consider previous medications, conduct a comprehensive assessment from the overall treatment process of colorectal cancer, and then select the best treatment plan
for patients.
If immunotherapy is given for the end-line treatment of non-liver metastatic MSS colorectal cancer, REGONIVO mode therapy (regorafenib + PD-1 inhibitor) can be considered, and more exploration
is needed for immunotherapy for liver metastatic MSS colorectal cancer.

A new direction of precision treatment - MRD detection is imperative

Professor Chen Gong

Sun Yat-sen University Cancer Center

Resectable patients with stage II-III colorectal cancer will relapse
despite postoperative adjuvant chemotherapy.
In this regard, Professor Chen emphasized that it is important
to find biomarkers that can predict the risk of recurrence and screen people who benefit from adjuvant therapy.
In recent years, the development of molecular detection technology has made NGS occupy an important position in personalized precision treatment of tumors, but with the gradual reduction of unknown targets, NGS may be "determined in the world"
.
At present, more and more clinical trials have confirmed that ctDNA MRD detection has broad application prospects and important potential value
for predicting recurrence and guiding treatment.

The latest results of the DYNAMIC study were presented at this year's ESMO conference, which conducted an exploratory analysis of subgroups of ctDNA-guided therapy and further analyzed the association
between ctDNA dynamic monitoring, carcinoembryonic antigen (CEA) levels and tumor recurrence.
The results showed that ctDNA analysis was more sensitive
to predicting distant recurrence than local recurrence in patients with stage II colon cancer.
Most postoperative ctDNA-positive patients can achieve ctDNA clearance with adjuvant chemotherapy and have a positive prognostic outcome
.
In addition, another real-world study to some extent validates the results of the DYNAMIC study, further confirming that the postoperative MRD status of colorectal cancer patients can be used to identify early recurrence risk, which can help make timely treatment decision adjustments (such as "adding" or "subtracting" on the basis of existing treatment options) to ultimately improve patient ^outcomes8,9
。

Fig.
4 Postoperative ctDNA positivity was significantly associated with shorter recurrence-free survival

Prof.
Chan concluded that ctDNA testing is of great value
in screening high-risk patients who can benefit from adjuvant chemotherapy.
In the future, it is hoped that more clinical trials will verify the guiding significance of ctDNA-based MRD on the decision-making of adjuvant treatment for colorectal cancer, help to achieve the optimal treatment plan adjustment for patients, and also expect more new molecular markers to replace traditional examinations (such as CT and other imaging examinations) in the future, so that patients can reduce radiation and save resources
for the country.

References:

1.
LEI Ziying, GUAN Tianpei, LUO Jiali, et al.
Rationality of intraperitoneal hyperthermic perfusion chemotherapy 5~8 weeks after resection of primary tumor of locally advanced colorectal cancer——Reflections based on COLOPEC research [J] .
Chinese Journal of Gastrointestinal Surgery,2019,22(12): 1115-1117.

2.
 Arjona-Sanchez A, Cano-Osuna MT, Gutierrez A, et al.
Adjuvant hyperthermic intraperitoneal chemotherapy in locally advanced colon cancer (HIPECT4): A randomized phase III study .
2022 ESMO abstract 314O.

3.
Saeed O, Lopez-Beltran A, Fisher KW，et al.
RAS genes in colorectal carcinoma: pathogenesis, testing guidelines and treatment implications.
J Clin Pathol.
2019 Feb; 72(2):135-139.

4.
DING Li, HAN Yiming, ZHENG Jie, et al.
KRAS gene mutations in colorectal cancer and their significance.
Journal of Clinical and Experimental Pathology.
2016,32(10):1156-1159.

5.
 Kuboki Y, Yaeger R, Fakih MG, et al.
Sotorasib in combination with panitumumab in refractory KRAS G12C-mutated colorectal cancer: Safety and efficacy for phase Ib full expansion cohort .
2022 ESMO abstract 315O.

6.
Klempner SJ, Weiss J, Pelster M, et al.
KRYSTAL-1: Updated efficacy and safety of adagrasib (MRTX849) with or without cetuximab in patients with advanced colorectal cancer (CRC) harboring a KRASG12C mutation .
2022 ESMO abstract LBA24.

7.
 Dasari NA, Lonardi S, Garcia-Carbonero R, et al.
LBA25 FRESCO-2: A global phase III multiregional clinical trial （MRCT） evaluating the efficacy and safety of fruquintinib in patients with refractory metastatic colorectal cancer[J].
Annals of Oncology, 2022, 33: S1391-S1392.

8.
 Tie J,Cohen J, Lahouel K, et al.
Circulating tumour DNA (ctDNA) dynamics, CEA and sites of recurrence for the randomised DYNAMIC study: Adjuvant chemotherapy (ACT) guided by ctDNA analysis in stage II colon cancer (CC).
2022 ESMO abstract 318O.

9.
 Cohen SA, Kasi PM, Aushev VN, et al.
Real-world monitoring of circulating tumor DNA reliably predicts cancer recurrence in patients with resected stages I-III colorectal cancer.
2022 ESMO abstract 319O.