Due to the continuous increase in global life expectancy and the high incidence of most cancer types in the elderly population, cancer diagnosis and treatment in elderly patients is receiving increasing attention.
However, little attention has been paid to whether tumor intrinsic features, such as histopathological manifestations or molecular features, vary by age, and how these differences may affect cancer care. In addition, patient age may be related to biological differences in the behavior of the tumor microenvironment, which has so far been insufficiently studied.
Recently, The Lancet Healthy Longevity published a review detailing several common types of cancers, compared with younger patients, there are significant differences in tumor histology and subtype distribution, and there are also differences in age-specific patterns of tumor mutations and other molecular changes. This information could provide new perspectives on more individualized cancer treatments, ultimately improving outcomes for older cancer patients.
Because breast, lung, and colorectal cancers are Chinese high-prevalence cancer types, today, this article will focus on sharing with readers the biological differences between these three cancer types as they change with age.
Screenshot source: The Lancet Healthy Longevity
breast cancer
Breast cancer is the most common cancer among women worldwide, with an average age of diagnosis of 62 years.
Compared with young people, the older the patient, the lower the incidence of malignancy. The proportion of subtypes of invasive ductal carcinoma (the most common subtype, also known as non-specific types of invasive breast cancer, which accounts for about 70% of breast cancers) continues to decline with age, while the proportion of invasive lobular carcinoma subtypes (about 15% of breast cancers) varies with age.
Older patients have fewer triple-negative breast cancers and HER2+ subtypes, and more luminal tumors, but all subtypes occur at all ages.
The older group is slightly less likely to develop HER2+, and HER2+ is overexpressed in about 15% of breast cancers. With age, the incidence of triple-negative breast cancer is much lower, and if diseased, it is more beneficial to the elderly population due to the fact that tumor biology presents less invasive ductal carcinoma and is a rare subtype (such as triple-negative large diadendrocyte carcinoma or lobular carcinoma).
Image credit: 123RF
As we age, the tumor mutation landscape also varies. For example, mutations in TP53, ATK1, GATA3, and MAP2K4 occur less often in older breast cancer populations (>65 years of age) compared to younger populations; in contrast, PIK3CA, MLL3, CDH1, and MAP3K1 mutations are more common.
The detection of interstitial tumor-infiltrating lymphocytes has become a reliable biomarker for the prognosis of breast cancer patients. The increase in interstitial tumor-infiltrating lymphocytes predicted response to neoadjuvant chemotherapy in patients with all molecular subtypes and was also associated with overall survival benefits for triple-negative breast cancer and HER2+ breast cancer. With age, a decrease in the percentage of interstitial tumor infiltrated lymphocytes was observed in breast cancer patients in general and in particular in triple-negative breast cancer patients.
Age-dependent changes in systemic immunity and perigma immunity have been reported in luminal B tumors. Age-related lymphocyte tumor infiltration was observed, immune structure changes (CD3+, CD5+, especially cytotoxic CD8+ cell density decreased), but further studies were needed for different breast cancer subtypes.
lung cancer
In general, older patients with non-small cell lung cancer (NSCLC) are more likely to be diagnosed with squamous cell carcinoma (SCC) and have a lower chance of developing adenocarcinoma. Squamous cell carcinoma is lower than adenocarcinoma at stage-specific 5-year overall survival.
The burden of tumor mutations increases with age. The review introduced mutations in EGFR gene, KRAS gene, BRAF gene and so on. Notably, specific tumor genomic EGFR changes vary by age: exon 21 L858R mutations occur more frequently in older populations, but in younger patients, exon 19 deletions occur more frequently. Notably, patient sensitivity to EGFR tyrosine kinase inhibitors depends on the underlying mutation subtype, with significantly longer progression-free and overall survival in patients with exon 19 deletions compared to L858R mutations.
KRAS mutations are common in NSCLC (20%-40%), often associated with poorer prognosis, a mutation that is more prevalent in older people.
BRAFV600E mutations may be more common in older adults (compared to melanoma), but BRAF inhibitors target very few BRAF mutations and there is no significant age difference.
In contrast, ALK, ROS1, and RET rearrangements (all genetic mutations targeted by tyrosine kinase inhibitors) are uncommon in older groups and more common in younger age groups aged 40 to 49 years.
Between different age groups, the expression of immune checkpoints PD-1 and PD-L1 did not change significantly with age. More research is needed to delve into the tumor microenvironment and explore its differences between older and younger patients.
Colorectal cancer
The median age at which colorectal cancer patients are diagnosed is about 70 years. There are significant biological differences between elderly colorectal cancer patients and younger patients.
About 80% of sporadic colorectal cancers follow the conventional adenoma-adenocarcinomacinosis pathway, in which disruption of epithelial renewal mechanisms is caused by exogenous (e.g., diet, smoking, alcohol, or obesity) or endogenous (e.g., chronic inflammation or oxidative stress), where adenoma polyps can evolve into malignant lesions and eventually lead to colorectal cancer.
About 20 percent of colorectal cancer cases do not originate from the traditional adenoma-adenocarcinoma carcinogenesis pathway, which appears to be more common in older patients. Among them, serrated polyps are most likely to be related to such cancerous changes, and there are rarely APC gene mutations. Moreover, the course of disease progression in these 20% of colorectal cancers is difficult to predict, and the time for malignant transformation may be short.
The incidence of right-half (proximal) colorectal tumors is higher in elderly patients, which accounts for about 50% of patients over 80 years of age.
At the molecular level, the prevalence of high CIMP type (CpG island methylated phenotype), microsatellite instability (MSI) and BRAF mutations is higher in elderly patients with colorectal cancer, especially in patients over 75 years of age, which may have far-reaching implications in treatment given the widespread use of targeted therapies and immunotherapy.
The immunological scoring system is associated with CD3+ and cytotoxic CD8+ T cell densities within tumors and at the edge of invasion. Review analyses showed that the effect of immunological scores on prognosis recurrence time appeared to be independent of age. However, the role of immunological scores in colorectal cancer management needs more research to better define its impact on the demand, subtype, and duration of adjuvant therapies.
brief summary
The review concludes by noting that aging clearly affects tumor biology. This review focuses primarily on biological features associated with the age at which cancer is first diagnosed, which are truly inherent in tumors and are not affected by previous treatments.
All in all, although there are different tumor subtypes and molecular changes in patients of all ages, the distribution of these features changes significantly with age. As we age and the immune system ages, the accumulated DNA damage may play a role, but it is not enough to explain all of the observations mentioned above. A better understanding of these characteristics and the biological processes behind them can help improve individualized cancer care for young and old.