Cancer is the enemy, but it is not one disease. Everyone’s tumors are quite a bit different, and in most cases, knowing what is different affects how it should be treated. When cancer is high-risk or advanced, guessing isn’t good enough. You’ve got to know everything you can.

The first smart step is to read the tumor itself. That’s what next-generation sequencing (NGS) does: it analyzes a piece of the tumor (from a prior biopsy or surgery) to identify the changes in its DNA and—ideally—its RNA. Those changes are the switches that make the cancer grow. NGS is like hiring a detective to uncover your tumor’s deepest, darkest secrets.

In a landmark NEJM 2022 study at Memorial Sloan Kettering, NGS revealed locally advanced rectal cancer patients who were mismatch-repair–deficient (MSI-H/dMMR), which is estimated to be 5-10% of all rectal cancer patients. In their trial, these patients, who were newly diagnosed, did not receive the standard treatments of surgery, chemotherapy, and radiation. Instead, they were given a PD-1 immunotherapy as their first treatment, and every single patient had their tumors melt away. The New York Times and other media outlets covered the remarkable remission of all of the patients in the study.

In about 20% of cases, the results of NGS point towards a standard, approved treatment, available in your oncologist’s office. However, studies have shown that next-generation tumor sequencing uncovers actionable targets in over 80% of patients.

That means at least 8 out of 10 patients have a more personalized option available when the NGS results are used to match to standard therapy and clinical trials. This has been our experience at Sagely Health as well. We help patients get the right test, keep paperwork and logistics moving, and—most importantly—turn results into action.

Not all NGS tests are the same. We prefer BostonGene’s Tumor Portrait Test on stored tumor tissue  (from a biopsy or surgical removal) because it gets the most information and integrates tumor DNA + matched normal DNA + tumor RNA with tumor-microenvironment insights. Caris (whole-exome DNA + whole-transcriptome RNA) is a more well-known close second, and Tempus (xT CDx + xR RNA) is also comprehensive option that include RNA.

However, be careful that these are not blood or saliva-based tests - they don’t just look at normal cells like other (genomic analysis) tests to look for hereditary causes of cancer.

See further details below.

‍Find a Clinical Trial

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How The NGS Test Works

A small piece of tumor that was already collected during a biopsy or surgery (the pathology lab usually stores it as “FFPE” blocks) is used.

What’s measured?

• DNA changes: mutations, extra/missing pieces, rearrangements; some tests also report MSI (mismatch repair status) and TMB (tumor mutational burden).
• RNA signals: which genes are “on/off,” plus gene fusions and splice changes. Including RNA often increases the chance of finding targets like MET exon 14 skipping and many fusions (NTRK/ALK/RET/ROS1).

How it works (step-by-step):

1. Your oncologist orders the test. (Need help asking?)
2. The lab requests your stored tumor sample from pathology.
3. The lab extracts DNA (and often RNA), sequences it, and analyzes the results.
4. A report comes back with findings and suggestions. The report is shared with your doctor, but once ready you can also request a copy from the company that completed the test.

(Results typically take about 2–3 weeks; this varies by lab and tissue quality.)

Why tissue rather than blood for the first pass?‍

Blood-based DNA tests (ctDNA) are excellent when tissue is hard to access or for ongoing monitoring, but when the goal is to find every realistic target at a decision point, tissue + RNA generally detects more fusions/splice events than DNA-only approaches.

First approvals - 2017 was a big year:

• FoundationOne CDx became the first FDA-approved broad tissue profiling test for solid tumors (324 genes) and also reports MSI and TMB (November 30, 2017).
• MSK-IMPACT (Memorial Sloan Kettering) received De Novo FDA authorization as a hospital tumor-profiling test (November 15, 2017).
• Oncomine Dx Target Test ushered in the FDA-cleared NGS companion-diagnostic era in lung cancer and has expanded to additional gene–drug pairs.

Since 2017, use has grown, but adoption is still uneven—often due to logistics and coverage—so many people who could benefit don’t get profiled at the right moment.

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Some examples of targets and matched treatments

These examples are here to show how specific findings can change treatment.

Important Note: Some genetic alterations are common in certain types of cancer and oncologists order small panels that only check for these common changes. Don't assume if you've been tested for some alterations that full NGS had been completed.

• Lung (NSCLC)
  
  • EGFR mutations → EGFR inhibitors
  • ALK/ROS1/RET/NTRK fusions → targeted kinase inhibitors
  • MET exon 14 skipping (often detected best with RNA) → capmatinib or tepotinib
• Colorectal (CRC)
  
  • MSI-H/dMMR → PD-1–based immunotherapy; in rectal cancer, this enabled non-operative strategies in selected patients at MSK.‍
  • BRAF V600E → encorafenib + cetuximab after chemo‍
  • HER2 amplification/overexpression (subset) → anti-HER2 combinations‍
• Breast‍
  
  • ‍HER2 amplification/overexpression → anti-HER2 therapies‍
  • PIK3CA mutation (HR+ / HER2−) → alpelisib + endocrine therapy‍
  • ESR1 mutation (HR+ / HER2−) → elacestrant (after prior endocrine therapy)‍
  • NTRK fusions (rare) → TRK inhibitors‍
• Cholangiocarcinoma (bile duct)
  
  • IDH1 mutation → ivosidenib
  • FGFR2 fusion/rearrangement → FGFR inhibitors‍
• Tumor-agnostic markers (work across many cancers)
  
  • MSI-H/dMMR or TMB-High → pembrolizumab (tumor-agnostic FDA approvals)‍
  • NTRK fusions → larotrectinib or entrectinib (tumor-agnostic approvals)

These are only a few examples. New treatments and new targets are being introduced via clinial trials on a weekly basis.

Comparing commonly used tissue tests

All three of these options perform DNA + RNA on tumor tissue, which helps surface both mutations and fusions/splice events.

• BostonGene Tumor Portrait™
  What’s notable: integrates tumor DNA + matched normal DNA + tumor RNA and includes tumor microenvironment analysis in one report, which can inform immunotherapy thinking.
• Caris (MI Profile / MI Tumor Seek)
  What’s notable: Whole-exome DNA + whole-transcriptome RNA (WES/WTS) across 20k+ genes, plus IHC/protein data; strong for detecting rare fusions/splice variants.
• Tempus xT CDx + xR (RNA)
  What’s notable: FDA-approved 648-gene tissue panel with companion-diagnostic claims, combined with whole-transcriptome RNA to detect fusions and MET exon 14 splice events.

Bottom line for patients: the DNA + RNA combination matters because some high-value targets are best found with RNA.

Other Cancer Diagnostic Tests

ctDNA (blood) for monitoring – Guardant360‍

A blood test that looks for tumor DNA fragments in the bloodstream. Useful when tissue is scarce and especially helpful for monitoring response or emerging resistance over time. It doesn’t require tumor tissue and can provide drug-matching information in many cases.

Proteomics for ADC targets – mProbe

ADCs (antibody-drug conjugates) target proteins on cancer cells. Traditional IHC tests one protein at a time and can use a lot of tissue. mProbe uses mass-spectrometry proteomics to measure dozens to 100+ proteins from very little tissue in a CLIA/CAP lab, which may help identify ADC targets for discussion with your oncologist.