Patients with secondary rectal cancer (SRC) after radiotherapy (RT) for prostate cancer have shorter survival compared with matched treatment-naïve patients, (1) but factors explaining this gap have been unclear.
Now, a new study by investigators at Memorial Sloan Kettering Cancer Center (MSK) has found distinct differences in patient characteristics, available treatment options, and tumor biologic characteristics that may explain the gap.
Their investigation found that patients with secondary rectal cancer after RT for prostate cancer were significantly older, less likely to have received total neoadjuvant therapy, and more often had tumors in the distal rectum and anterior rectal wall compared to a control group of patients with primary rectal cancer (PRC). They also had significantly lower tumor mutational burden, fewer APC alterations, and higher rates of frameshift deletions and SMAD4 inactivation compared to the control group. (2)
The insights, published March 18, 2025, in JAMA Network Open, may improve the clinical management of SRC after prostate cancer.
“While the differences in survival outcomes may have traced to differences in treatment, secondary rectal cancer status was an independent factor associated with distant metastasis and lower disease-free survival,” said computational oncologist Francisco Sanchez-Vega, PhD, Head of Real-World Data Analysis at The Halvorsen Center for Computational Oncology at MSK and senior author of the study. “It is tempting to speculate that patients with secondary rectal cancers may be good candidates for immunotherapy. However, future studies among larger, independent cohorts of patients with secondary rectal cancer after prostate cancer are required to investigate this hypothesis.”
Secondary Rectal Cancer After Prostate Cancer
In the United States, the lifetime risk of developing prostate cancer is 11%. (3) There are approximately 300,000 new diagnoses annually, and about 3.4 million men are currently living with the disease. (4)
About one in four patients with prostate cancer receive RT in the form of external beam radiotherapy (EBRT), brachytherapy (BRT), or both. (5)
Population studies have shown that patients with prostate cancer who undergo RT have an increased risk of developing SRC, (6) (7) (8) (9) (10)(11) defined as originating in the field irradiated during initial tumor treatment and developing at least five years after RT. (8) (9)
Study Design
The first authors of the manuscript were Dana Omer, MD, a colorectal oncology research scholar working from 2021 to 2023 in the lab of Julio Garcia-Aguilar, MD, PhD, Chief of the Colorectal Service at MSK, and Farheen Shah, MSc, a computational scientist working under the supervision of Dr. Sanchez-Vega. The case-control study was conducted in collaboration with MSK colorectal surgeons, radiation oncologists, pathologists and biostatisticians.
The research team identified 64 male patients with colorectal adenocarcinoma and a history of prostate cancer treated at MSK between February 1994 and September 2022 who developed an adenocarcinoma located 12 cm or less from the anal verge diagnosed at least five years after RT. They also identified a control group of 604 male patients with PRC without a history of prostate cancer or pelvic RT treated during the same period. (2)
Dr. Sanchez-Vega and colleagues examined overall survival (OS), disease-free survival (DFS), local recurrence-free survival, and distant recurrence-free survival between these two groups after propensity score matching.
They also analyzed 31 available tumor specimens using MSK-IMPACT®, which identifies somatic mutations, copy number changes, and fusions in a panel of more than 500 cancer-associated genes. Additionally, they performed whole-exome sequencing on 17 of the 31 samples that had sufficient material for capture and conducted computational genomics analyses to explore differences in mutational signatures and types of variants. They distinguished oncogenic somatic alterations from variants of unknown significance using the OncoKB® knowledge base. (12) (13)
Study Findings
There were several notable differences in characteristics between patients with SRC and those with PRC, as follows: (2)
Differences in clinical characteristics:
- older, with a median age of 78 versus 55
- more distal rectal tumors (58% versus 23%, p < 0.001)
- more anterior rectal wall tumors (35% versus 14%, p < 0.001)
- less likely to have received total neoadjuvant therapy (52% versus 94%, p < 0.001)
Differences in available treatment options. The analysis revealed an increasing use of re-irradiation treatment in patients with SRC over time. All 11 patients with SRC treated with neoadjuvant therapy until 2014 received chemotherapy only, whereas 14 of 22 patients treated after 2014 (64%) received re-irradiation.
Differences in oncologic outcomes. SRC patients had a shorter 5-year OS (46% versus 65%, p = 0.01) and a shorter DFS (40% versus 71%, p = 0.006) when compared to clinically matched PRC patients (m-PRC).
Differences in targeted DNA sequencing results. MSK-IMPACT® results for 31 SRC tumors versus 62 m-PRC patients showed the following:
- lower tumor mutational burden (4.4Mb versus 6.1Mb, p = 0.006)
- lower frequency of APC alterations (48.4% versus 72.6%, p = 0.04)
- higher rates of SMAD4 inactivation (25.8% versus 8.1%, p = 0.03)
Differences in whole-exome sequencing results. Data from 17 SRC tumors showed a higher rate of frameshift deletions, inframe deletions, and splice site variants than those found in 28 unmatched PRC tumors.
Transforming Data into Clinically Actionable Insights
The Halvorsen Center for Computational Oncology at MSK unites data science, artificial intelligence, and algorithm development to analyze vast patient and experimental datasets to advance the understanding of cancer biology and discover clinically actionable insights for improving patient outcomes. Read more.