Early Cancer Detection Will Save More Lives

Cancer deaths due to failure of early detection

According to the American Cancer Society researchers, it is estimated that there will be more than 600,000 people die of cancer, and 1.9 million new cancer cases in the US in 2021 alone. Seventy-one percent of the patients who died of cancer did not get common cancer screening and it is too late when they get diagnosed with cancer. The five-year survival rate is four-fold higher if the cancer is diagnosed earlier than at a later stage. Average 5-year survival at early stage is 91%, while average 5-year survival at late stage is 26%. You may say that there is no meaning if cancer is detected early as there is no treatment. In fact, literature and practice guidelines indicate that all early cancers have treatments. Therefore, the earlier the cancer is found, the better control and survival outcome would be thanks to surgical removal or therapy by drug regimens.

The development process of cancer, cancer diagnosis, and therapy

Cancer development goes through different stages. At the very beginning, the normal cells become malignant, and cancer starts to grow. At this stage, cancer is undetectable and there are no symptoms. Then, cancer will continue to grow and at any point, a small portion of the cancer cells will become metastatic. With metastasis becoming widespread, cancer will kill the patients. Most of the cancers are detected at a later stage after metastasis when symptoms already appeared. At this stage, the traditional cancer diagnosis is through detection methods such as imaging or specific DNA or protein biomarkers. Although different therapy strategies including a single or combination of radiation therapy, chemotherapy, targeted therapy, or immunotherapy are used once the cancer is diagnosed at later stages, cancer remains harder to cure at this stage.

Challenges of accurate early cancer detection

Early detection can save lives when cancer cells start to grow without symptoms. Currently, only a few types of cancer can be diagnosed at an early stage: colorectal cancer by colonoscopy; breast cancer by mammography; prostate cancer by prostate-specific antigen; cervical cancer by cervical cytology such as Pap test; skin cancer by a visual check. Due to technical difficulties and challenges, most cancer types are only diagnosed late when signs and symptoms start to appear. It is beneficial to have a universal sampling and screening method to detect all different types of cancer at an early stage.

However, early cancer detection faces challenges. For instance, the tumor may be too small to be detected by even the newest imaging technique at an annual check; Fast-growing tumors may need more frequent checks and frequent imaging is not practical and expensive. Although some biomarkers such as carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) may help diagnose cancer early, still some early cancer without any symptoms can be missed.

Liquid biopsy as a powerful potential screening tool for early cancer detection

Traditionally cancer diagnosis involves imaging or biomarker identification, or the combination followed by tissue sampling. As we said above, cancer may escape early detection by these traditional methods. Although tissue biopsy can mostly provide an answer at this stage, it has other disadvantages: (1). The biopsy may miss the tumor cells or does not get sufficient samples for accurate testing results; For example, in non-small cell lung cancer (NSCLC), tissue biopsy was inadequate for genotyping. (2) Biopsy can be so invasive and painful that patients can not repeatedly provide samples, which is necessary for cancer monitoring in progression and treatment response. (3). It is not realistic to use tissue biopsy for cancer screening when it is not sure where cancer may be formed.

Recently, liquid biopsy as an emerged technology has gained great traction for cancer screening and early cancer detection. Liquid biopsy is minimally invasive and can sample the cancer cells, cancer cell DNA (commonly called cell-free DNA, or cfDNA), RNA (such as non-coding RNA), and exomes (extracellular vesicles). Liquid biopsy as a method of sampling can provide great benefits for cancer patients in the following ways:

• Early cancer detection
• Regular cancer diagnosis and progression monitoring
• Cancer treatment and response to traditional radiation or chemotherapy or targeted drug therapy
• Cancer prognosis (for future survival outcome)

cfDNA and early cancer detection

Among the biological materials mentioned above in liquid biopsy samples, cfDNA is the most studied material for cancer detection. cfDNA is released from either normal cells or tumor cells (ctDNA) by mechanisms such as apoptosis, necrosis, or active release.

Recently, cfDNA mutation, cfDNA methylation, the cfDNA level, or the ratio of cfDNA levels before and after a treatment all have been used either for early cancer detection, cancer progression, or drug response monitoring. For instance, some of the cfDNA assays are more sensitive and provide better specificity than the regular CEA or CA biomarkers. Since Cancer gene mutations happen a decade before cancer diagnosis, mutation detection in cfDNA can be one or more years earlier than regular cancer diagnosis and may win the precious time for cancer therapy at an early stage. DNA methylation assay has been successfully used for the early detection of four types of cancer in a high-risk population. The combination of deep DNA sequencing by next-generation sequencing (NGS) and methylation as an early detection tool can even identify the critical mutations in different cancer types.

Caveat of early cancer detection

First of all, since the cfDNA level is generally quite low for healthy individuals, ranging from 1 to 10 ng per ml of plasma, and the cfDNA has a short half-life, it may be difficult to get sensitive tests for early cancer detection. The early screening tests can generate false-negative results due to the limitation in sensitivity and availability of the sample amount. If the test does not have high specificity, false-positive results can cause emotional pain and unnecessary cost to the patients.

In addition, slow-growing cancer detected earlier may cause overdiagnosis or overtreatment issues—cancer may not cause a problem in a lifetime but is detected and treated without any benefit. It is also critical to know if the cfDNA mutations can differentiate benign from malignant tumors before the cfDNA can be used as a powerful biomarker for cancer.

Finally, although gene mutation detection may provide critical information for early diagnosis, cancer mutations may not be the cause for cancer. In fact, a recent study has shown that cancer driver gene mutations can exist in normal tissues. This adds more complexity in our understanding of how cancer is initiated, which would be critical for the cure of cancer; mutation detections may only provide guidance for shrinking cancer, but not the cure.

CfDNA Applications for Cancer Diagnostics at DiaCarta

At DiaCarta, cfDNA has been used in diagnostics products for cancer detection including early cancer detection, therapy monitoring, and target therapy resistance mutation detections.

Cancer mutations: the coloscape assay is developed for testing both colorectal cancer as well as pre-cancer (advanced adenoma) mutations based on our proprietary XNA technology. The assay provides more than 90% clinical sensitivity and 95 to 100% specificity for colorectal cancers and 62.5% clinical sensitivity for pre-cancers due to the high analytical sensitivity (0.1 to 0.5% variant allele frequency, VAF). The test sensitivity and specificity is significantly better than the routine FIT (the fecal immunochemical test) assay. The clinical studies have shown the promise of the assay used as a triage for FIT-positive patients before testing by colonoscopy.

Therapy monitoring: the cfDNA level has been widely studied and is thought to be potential biomarker in people with a variety of diseases including cardiovascular diseases and cancer. The ratio of cfDNA level before and after therapies such as chemical or radiation therapy has also been studied and used as potential biomarkers for therapy monitoring and prognosis. cfDNA quantification test developed at DiaCarta has great advantages compared to other cfDNA quantification methods as it does not need DNA isolation, only needs 10 ul of plasma samples, and has less hands-on work. The assay has been successfully used for therapy monitoring in prostate cancer, non-small cell lung cancer (NSCLC), and gastric cancer.

Resistance mutation detection for targeted therapies: Early cancer mutation detection needs highly sensitive analytical assays. Similar to our Coloscape assay, we also developed single gene mutation assays (QClamps) that cover the hot-spot mutation of cancer driver genes. The single BRAF assay using either qPCR or Sanger sequencing can be easily used for high-sensitivity diagnosis of BRAF V600 mutations. The accurate and sensitive detection of these important mutations is important before targeted therapies are applied and are critical to finding drug resistance mutations.