A multiple metastatic colon cancer patient with extra-long survival and acquired BRAF mutation: case report and literature review

doi:10.21203/rs.3.rs-5243965/v1

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Case Report

A multiple metastatic colon cancer patient with extra-long survival and acquired BRAF mutation: case report and literature review

https://doi.org/10.21203/rs.3.rs-5243965/v1

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For colorectal cancer patients, metastasis is a major cause of high mortality and short survival. Precision medicine has led to significant advances in targeted therapy and immunotherapy in the treatment of colorectal cancer, providing more options for patients with mCRC and eventually improving their prognosis. However, the use of these drugs is limited by pre-existing intrinsic resistance mechanisms or the ability of cancer cells to acquire resistance. This report presents a colorectal cancer patient who survived 12 years. After the first palliative resection for descending colon cancer, this patient had experienced local recurrence, splenic and diaphragmatic metastases, splenic fossa and incisional implant metastases, renal metastases, and liver metastases. The patient underwent five surgical resection procedures and benefited from surgery combined with chemotherapy. The disease was initially controlled with first-line treatment when the patient developed liver metastases. After the metastases progressed, next-generation sequencing (NGS) revealed the patient's acquired genomic alternation, BRAF V600E. This case highlights the importance of combining local and systemic therapy and the need to be aware of acquired genomic alternations.

Metastatic colorectal cancer (mCRC) is one of the leading causes of death in patients with the disease. Patients with mCRC have a 5-year survival rate of only 14%, with a median survival of 15.4 months.^{1, 2} A combination of chemotherapy, radiotherapy, and surgery can be used to treat colorectal cancer (CRC) and metastases to slow cancer progression and extend patients' survival.³ The MDT of surgeons, oncologists, and radiation oncologists collaborate to develop an integrated treatment plan. Systematic chemotherapy is an essential treatment option for metastatic CRC. Besides, precision medicine provides more options for mCRC patients, ultimately improving their prognosis.

In mCRC patients, combining anti-epidermal growth factor receptor (EGFR) antibodies, including cetuximab and panitumumab, with other chemotherapy regimens significantly improves survival.⁴ However, these drugs are often limited by the natural or acquired resistance of the patients. In particular, patients have been reported to develop anti-EGFR antibody resistance during anti-tumor therapy. This resistance is usually due to mutations in KRAS, NRAS, BRAF, and EGFR,^{5, 6} posing a challenge to the treatment of patients with advanced cancer.

In this study, we report on a patient with multiple metastatic colorectal cancer. The patient survived 12 years but discovered an acquired BRAF mutation following second-line chemotherapy. The MDT team developed treatment plans for the patient, achieving an above-average survival time and providing a reference for other mCRC patients.

A 49-year-old man came to our hospital due to “bloody stool with increased frequency for 1 year” in November 2011. Three weeks earlier, the patient had suffered a myocardial infarction. Computed tomography (CT) scan showed descending colon cancer with peripheral lymph node enlargement (Fig. 1A). Gastroscopy could not be performed successfully due to bowel obstruction. The patient underwent a palliative resection of the descending colon on 10 February 2012. Post-operative pathology reported moderately differentiated adenocarcinoma of the descending colon with full-thickness stromal invasion (pT4bN0M0). Then, the patient received one cycle of XELOX (oxaliplatin and capecitabine) as adjuvant chemotherapy in March 2012. A follow-up examination showed CEA elevation in August 2012, while no recurrent or metastatic lesions were seen on CT images (Fig. 1B). Then the patient received six cycles of XELOX with the same regimen as before. In May 2013, the patient underwent a colonoscopy, which suggested a bulging lesion in the descending colon, together with CT findings of local bowel wall thickening (Fig. 1C). The colonoscopy pathology subsequently reported a definite local recurrence of adenocarcinoma of the descending colon. On May 18, 2013, the patient underwent local tumor resection for colon cancer recurrence. Considering the patient's history of myocardial infarction, he was treated with the less cardiotoxic chemotherapy of raltitrexed and oxaliplatin for 4 cycles. The disease was assessed as progression-free by CT in October 2013 (Fig. 1D). In March 2014, the follow-up CT examination suggested there was a splenic space-occupying lesion, and then the patient received spleen and diaphragm metastasectomy (Fig. 1E). Follow-up CT scans showed no progression of the disease (Fig. 1F-I). On 20 October 2016, CT showed metastases of colorectal cancer in the splenic recess and the incision (Fig. 1J-K). The patient received metastasectomy in October 2016. The patient received regular follow-up CT scans (Fig. 1L-M) until 8 May 2020, when a left renal space-occupying lesion was detected by abdominal CT (Fig. 1N). On 23 May 2020, the patient underwent abdominal tumor resection, left nephrectomy, and partial small bowel resection. In January 2021, liver metastases from colon cancer were discovered by a CT scan, which showed multiple hypodense foci in the liver (Fig. 2A).

After liver metastases were detected, the patient received one cycle of FOLFIRI (irinotecan, leucovorin and fluorouracil). The NGS analysis was performed on formalin-fixed, paraffin-embedded (FFPE) tissue, showing no mutations in KRAS, NRAS, BRAF, and HER2 (Fig. 2J). Cetuximab (EGFR inhibitor) was added to the treatment on 01 February 2021. The curative effect was assessed as partial response (PR) according to the enhanced CT result on 24 March 2021(Fig. 2B). The patient continued to receive eight cycles of FOLFIRI plus cetuximab. The curative effect was evaluated as stable disease (SD) on 25 May (Fig. 2C). The patient was treated with cetuximab plus capecitabine as a maintenance therapy for one year from July 2021 until the progression of the disease on 13 July 2022 (Fig. 2D-E). In August 2022, the patient received the second-line chemotherapy of bevacizumab plus FOLFIRI. A CT scan performed on 5 September showed that the liver metastases had progressed further (Fig. 2F). Given the patient's disease progression, the patient underwent next-generation sequencing again. Samples for NGS are obtained from FFPE and circulating DNA in the peripheral blood. The NGS results reported a BRAF mutation on 19 September (Fig. 2J). According to the NGS result, the patient decided to receive the third-line chemotherapy (regorafenib 80mg) on 21 September.

After one cycle of regorafenib, the serum biomarker showed a decrease in CEA from 113.16 to 45.88ng/mL (Fig. 3). Tislelizumab (an anti-PD⁃1 drug) was added to the treatment on 18 October. On 3 January 2023, due to COVID-19 infection, the patient had to suspend the antineoplastic therapy for 1 cycle. The symptoms of pneumonia improved with antiviral symptomatic treatment. Follow-up CT scans showed that the patient’s metastases were stable (Fig. 2G-H). On 2 May, the patient was re-infected with COVID-19. As a result, chemotherapy was again suspended for one cycle. The latest CT scan evaluated the patient’s disease as progressive disease (PD) (Fig. 2I). The patient underwent NGS test on the blood sample on 8 September (Fig. 2J). Then, the patient received cetuximab in combination with dabrafenib. He received last treatment on 27 September. Unfortunately, the patient could no longer tolerate the anti-tumor therapy due to his poor general condition with a performance status score > 2. The patient passed away on 21 October. The timeline of the disease evolution and treatment is shown in (Fig. 4).

During the course of the disease, the patient underwent five surgical resection procedures for the primary lesion, local recurrence, and distant metastases. The patient's initial pathological stage was T4bN0M0 (ⅡB). According to the SEER database, the five-year survival rate for CRC patients undergone radical colon cancer surgery was 60.1% for stage IIB. The median overall survival (OS) for treated mCRC patients is approximately 30 months.⁷ In this report, the patient survived almost 12 years. MDT helped prolong the patient's survival. When the patient was diagnosed with colorectal cancer in 2011, his surgery, radiotherapy, and chemotherapy regimens were all developed by an MDT. MDT has been advocated as the standard of care in modern oncology as it can reduce perioperative morbidity and mortality and improve patients’ long-term survival.⁸ In terms of this patient's extraordinarily long survival, the MDT played a crucial role throughout by rationalizing the combination of local and systemic treatments.

When liver metastases were discovered, we first gave this patient 1 cycle of FOLFIRI chemotherapy. After we confirmed that the NGS was KRAS/NRAS/BRAF wild-type, the patient was treated with FOLFIRI plus cetuximab. Five months later, the patient received one-year maintenance therapy of cetuximab plus capecitabine. After that, the patient’s disease progressed. We then decided to give the patient 2 cycles of FOLFIRI in combination with bevacizumab as a second-line treatment. Bevacizumab is an anti-vascular endothelial growth factor (VEGF) monoclonal antibody that works by blocking tumor angiogenesis.⁹ According to the BEBYP trial, patients in the bevacizumab-chemotherapy arm had a median PFS of 6.8 months. However, this patient’s PFS was only 1 month. It indicated that this patient has primary resistance toward bevacizumab. Resistance to anti-VEGF therapy is usually due to the activation of bypass angiogenic pathways other than the VEGF pathway. Alternatively, it may be related to tumor stem cell activation, intratumoral hypoxia, and other aspects of the tumor microenvironment. However, the key mechanisms underlying the development of bevacizumab resistance are not fully understood.^10–13

After disease progression, we re-tested NGS, which showed a BRAF V600E mutation. Acquired genomic alterations (Acq-GA) are not uncommon in the later-line treatment of anti-EGFR antibodies.^{6, 14, 15} It occurs in 62% of patients with mCRC.¹⁶ In a study of 22 patients who developed resistance after cetuximab therapy, 7 had KRAS mutations, 2 had BRAF mutations (both V600E), 2 had HER2 amplification and 4 had MET amplification.⁶ It can be inferred that BRAF mutations are a relatively rare genetic alteration in acquired resistance to anti-EGFR antibodies. Besides, Acq-GAs are rarely seen in the first-line treatment. A prospective-retrospective study figured out the incidence of major acquired genomic alterations in first-line cetuximab-chemotherapy. The results showed that Acq-GA occurred at progression in only 4 of 61 patients (6.6%) treated with cetuximab chemotherapy, an incidence similar to that of bevacizumab chemotherapy (7 of 69 [10.1%]). However, there is a lack of research into the characterization of resistance to anti-EGFR-chemotherapy for mCRC in the first-line setting.¹⁶

CRC with BRAF V600E mutations is often associated with a poor prognosis, the median survival of only 12 months.^17–20 In the phase III BEACON CRC trial, the BRAF inhibitor encorafenib was used in combination with cetuximab as a second/third-line treatment for patients with BRAF V600E-mutated mCRC and showed better efficacy and tolerability.²¹ In addition, BRAF and EGFR inhibitors have been shown to induce a transient MSI-H phenotype in preclinical models of CRC with microsatellite stable (MSS) and BRAF V600E mutations and may enable tumors to respond to immunotherapy with anti-PD-1 antibodies, such as nivolumab. A phase I/II clinical trial showed that encorafenib, cetuximab, and nivolumab were effective and well tolerated in patients with MSS, BRAFV600E-mutated mCRC. It can be concluded that patients with BRAF mutations may benefit from a combination of BRAF inhibitors and PD-1 inhibitors. Following the detection of the BRAF V600E mutation, our patient should have been given a BRAF inhibitor, but given the patient's financial considerations, we opted for a last-line regimen of regorafenib.

Regorafenib is an oral, broad-spectrum multi-kinase inhibitor. It can target at BRAF to exert its anti-tumor activity.²² It has a survival benefit in mCRC patients that have progressed after all standard therapies.²³ In addition, in the phase Ib trial of REGONIVO, the combination of regorafenib and nivolumab demonstrated good safety and anti-tumor activity in MSS / pMMR CRC patients who had received at least 2 previous lines of chemotherapy, with objective response rate (ORR) reaching 33%, beyond ORRs shown by regorafenib or anti-PD-1 monotherapy.²⁴ In this case, we chose tislelizumab plus regorafenib as the patient’s later-line therapy. The patient has survived over 10 months after receiving regorafenib. The survival has reached 6 months after receiving regorafenib plus an anti-PD-1 antibody. It can be inferred that patients with liver metastases can also benefit from regorafenib combined with immunotherapy. But it is only part of the story, which needs to be confirmed in larger studies.

In conclusion, in this case, we can learn the benefits of local combined systemic therapy as well as the reasonable application of chemotherapy, targeted, and immunotherapy in prolonging the survival of patients with metastatic colorectal cancer. However, this case is only a reference and needs to be validated in a larger number of patients.

CRC, colorectal cancer; mCRC, metastatic colorectal cancer; NGS, next-generation sequencing; MDT, multidisciplinary team; EGFR, epidermal growth factor receptor; CT, computed tomography; FFPE, formalin-fixed, paraffin-embedded; PR, partial response; SD, stable disease; PD, progressive disease; OS, overall survival; VEGF, vascular endothelial growth factor; acq-GA, acquired genomic alterations; MSS, microsatellite stable; ORR, objective response rate; PFS, progression-free survival

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Ethics approval and consent to participate

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Consent for publication

We obtained informed consent from the patient for publication of his data and the publication of this case report.

Funding Information

This study was funded by grants from Jiangsu Provincial Department of Science and Technology (Grant Number BE2023717), Suzhou Municipal Science and Technology Bureau (Grant Number SKY2022006, SLJ202011 and SLT201959), Jiangsu Commission of Health (Grant Number M2020043) and China Digestive Tumor Clinical Research Public Welfare Project (Grant Number P014-038).

Competing interests

The authors have no conflict of interest.

Author Contributions

Authors FG and JS designed the clinical treatment for the patient and critically reviewed the report. YC and ZK collected the clinical data, wrote the manuscript, and drew the figures. YL, YW, KL, CL, JY, LZ and HG participated in patient treatment and provided comments and interpreting the results. LH, PG, and HC interpreting the results. YW revised the manuscript.

Availability of data and materials Data are to be provided upon request to the corresponding author.

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No competing interests reported.

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A multiple metastatic colon cancer patient with extra-long survival and acquired BRAF mutation: case report and literature review

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