Colorectal cancer: in 12 patients it disappears completely thanks to ablative immunotherapy

Without surgery, no radio or chemotherapy. Total recovery was possible for 12 young patients with locally advanced colorectal cancer and a deficiency in the function of the DNA repair system (MMR), a condition unfortunately associated with a decrease in survival and a reduced response to chemotherapy. conventional.

Yet, precisely because of this characteristic, the patients obtained a 100% response to the dostarlimab immunotherapy treatment. Extraordinary results presented at the World Congress of Oncology (abstract 16) and simultaneously published in the New England Journal of Medicine by researchers at the Memorial Sloan Kettering Cancer Center (MSK).

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The instability of microsatellites and the Mmr deficit

Microsatellite instability is present in approximately 10-15% of colon and stomach cancers and is the major genetic alteration found in hereditary non-polyposis colorectal cancers (HNPCC or Lynch syndrome). The instability status of microsatellites is considered an indicator of a functional deficiency of the DNA repair system (MMR).

Recent studies have shown that MMR malfunction is a predictor of response to anti-PD-1 antibody therapy, i.e. a greater response to immunotherapy was observed than in tumors without MMR defects. “Because metastatic colorectal cancer with mismatch repair deficiency (MMR) responds to Pd-1 inhibitor – explained Andrea Cercekco-director of the Center for Young Onset Colorectal and Gastrointestinal Cancer at Memorial Sloan Kettering Cancer Center – we hypothesized that even locally advanced ones could be sensitive to this type of therapy to the point of avoiding chemoradiotherapy and surgery altogether. “.

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I study

The researchers conducted a prospective study of 12 patients with a mean age of 54 years (62% women) and with stage 2 and 3 rectal adenocarcinoma with mismatch repair deficiency. These patients were given an anti-PD-1 monoclonal antibody, dostarlimab alone, every three weeks for six months, followed by standard chemoradiotherapy or surgery. For patients who achieved a complete clinical response, standard treatments could have been avoided altogether.

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An immuno-ablative therapy

All 12 patients who started treatment had at least six months of follow-up and achieved a complete clinical response with no evidence of tumor from MRI, PET scan, endoscopy, rectal examination, or biopsy. To date, no patients have required chemoradiotherapy or surgery, and no cases of progression or relapse have been noted during follow-up (up to 25 months). No serious adverse events were observed.

Tears and happiness for patients

In short, the tumors of these 12 patients ‘simply’ disappeared. Like a virtual scalpel, the monoclonal antibody removed the neoplasm. Disbelief, happiness and gratitude are the feelings of these young bearers of what could represent a turning point in the treatment of this type of cancer.

In a video posted on the Memorial Sloan Kettering Cancer Center website, patient Imtiaz says: “The first thing I did after learning that the tumor was gone was to call my mother: we cried with happiness together on the phone. It’s something that is changing my life. “

And with a smile that never seems to want to end, Nisha tells of the day she had her checkups after the treatment: “I asked the doctors where the tumor was, I couldn’t see it anymore and I was afraid it had moved, but then Doctor Cercek told me that he had disappeared completely: for me it was like a miracle “.

The impact on the quality of life

Of course it is a study with few subjects and caution is a must, but the expectations are very high especially for younger patients for whom avoiding the most aggressive treatments can mean a lot. “Surgery and radiation have permanent effects on fertility, sexual health, bowel and bladder function”, explained Cercek, adding: “The implications on quality of life are substantial especially when one considers that the incidence of cancer rectum is increasing in young adults. “

The next frontiers

Great enthusiasm also on the part of Luis Alberto Diazhead of the Division of Solid Tumors at MSK and coature of the study: “Although a longer follow-up is needed to assess the duration of response – he said – this treatment is changing the practice for patients with locally advanced rectal cancer with mismatch repair deficiency (MMR) “.

His previous study led to a paradigm shift in the treatment of patients with this type of cancer in 2017, when the FDA announced the first pan-tumor approval for adult and pediatric patients with metastatic MMR tumors who have progressed after previous treatment. .

This was the first ‘agnostic’ approval made by the FDA. “As our research progresses – concluded Diaz – we expect the PD-1 inhibitor to be evaluated in other malignant mismatch repair cancers including those of the pancreas, stomach and prostate not yet metastatic in the neoadjuvant phase. which could open the door to a similar pan-tumor approach in metastatic disease. ” Dostarlimab is already approved by the US Food and Drug Administration for use in the treatment of recurrent or advanced endometrial cancer with Mmr. For rectal cancer this is off-label use.

Colorectal cancer in Italy

In our country, almost 44 thousand new cases of colorectal cancer are estimated every year, the second most frequent neoplasm in the Italian population after that of the breast. In about 20% of cases the disease is unfortunately discovered when it is already metastasized. However, not all colon cancers are the same.

A small proportion of these tumors, equal to about 5% of the total, have a particular molecular characteristic, the instability of microsatellites which generates a high load of mutations in the tumor DNA. This type of neoplasm is unfortunately associated with a decrease in survival and a lower response to conventional chemotherapy compared to colon cancers without high microsatellite instability.

Colorectal cancer mainly affects people over the age of 60 and is strongly influenced by lifestyles. In fact, the most important risk factors are represented by a diet rich in red meats and sausages, smoking, obesity and low physical activity. Survival has increased significantly in recent years and 65% of patients overcome the disease, but when the cancer is found at an advanced stage, the chances of defeating it are limited.

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