Got an Actionable Mutation, but Your Targeted Drug Isn’t Working? Here’s Why and What You Can Do About It.

Your daughter just turned 3 last week and now you have been diagnosed with metastatic HER2-positive breast cancer. It’s an aggressive type of tumor but fortunately there is drug that was designed specifically for HER2-positive tumors. Your insurance approves it and you start treatment right away.  So, you’re grateful for the enormous progress cancer research and especially precision medicine has been able to accomplish: the right drug for the right tumor.  

Then the next scan shows that your cancer is still growing. Why? How could that have happened?

The Ingenuity of Precision Medicine

Precision oncology is based on an extraordinarily compelling concept. Analyze the genetic abnormalities of your tumor, identify the important molecular driver, and select the drug designed to selectively interfere with that driver. And for some patients it has worked remarkably well.

However, most patients don’t have actionable mutations.  For example, when according to the National Cancer Institute’s Molecular Analysis for Therapeutic Choice (MATCH) trial, a targeted therapy could have been clinically assigned in only 26.4% of cases.¹ That is consistent with a recent meta-analysis of real-world genomic profiling studies where only 22.4% of patients had genomic alterations considered to be clinically relevant.² In other words, only 1 in 4 patients have actionable mutations.

“Targetable” does not mean “Likely to Respond”

What is worse, even when a target exists and a matched drug is available, response is far from guaranteed. For example, the package insert of Enhertu™ (trastuzumab deruxtecan) shows that the objective response for HER2-positive breast cancer is just about 60%.³ That is actually significant progress compared to the previous therapies, but it is not 100% either. And this can range from about 20% for Braftovi® (encorafenib) plus cetuximab in previously treated BRAF V600E-mutated colorectal cancer⁴ to about 77% for Tagrisso® (osimertinib) in EGFR-mutated metastatic lung cancer.⁵

Tumor / Biomarker	Matched Therapy	Response
EGFR-mutated NSCLC	Tagrisso® (osimertinib)	77%⁵
HER2-positive breast cancer	Enhertu® (trastuzumab deruxtecan)	60%³
PIK3CA-mutated breast cancer	Piqray® (alpelisib)+fulvestrant	36%⁶
BRCA-mutated pancreatic cancer	Lynparza® (olaparib)	23%⁷
BRAF-mutated colorectal cancer	Braftovi® (encorafenib)+cetuximab	18%⁴

Thus, while the traditional precision medicine concept is compelling, it can give a false sense of our ability to accurately treat and control cancer today. After all, tumors contain multiple genomic abnormalities, parallel signaling pathways, resistant subclones, differences in gene expression and protein activity, and complex interactions with their surrounding microenvironment. Hence, a mutation can identify an attractive therapeutic target without proving that blocking that target will actually stop that particular tumor.²,⁸

Limitations of Established Cancer Diagnostics

Current cancer diagnostics share one conceptual limitation. It is largely based on non-viable, preserved tissue. Pathology classifies tumor type and genomic testing and other biomarkers provide the mechanistic framework which therapy should work. But none of those methods test how a patient’s tumor actually responds to various treatment options. This begs the question why not?  

One reason is that testing freshly removed live tumor samples is logistically more difficult than working with formalin-fixed, preserved tumors. Thus, despite decades of research, it is not standard of care, nor covered by insurance yet.

Testing Which Drugs Do Actually Work for Your Cancer

However, there is ample of evidence that functional profiling assays can predict whether a drug is likely to work fairly accurately and two recent studies have even shown a significant increase in progression free or overall survival in patients with recurrent ovarian cancer and glioblastoma.⁹,¹⁰ And for breast cancers, Volm et al. listed 7 studies predicting sensitivity and resistance in 75% to 94% of cases.¹¹

How to Find a Clinical Lab and Get Tested if Current Therapy Has Stopped Working

Given that strong evidence for functional profiling has only emerged recently, this is not part of today’s guidelines yet and many oncologists may not be familiar with those latest developments. Thus, the best way is to start with your own research and identify the test that may be best for you, contact those labs to see whether you may qualify for the test and if so, ask your doctor to order it for you.

The latest and likely most advanced and accurate laboratory developed test (LDT) has been developed by SageMedic Corp. as it combines three clinically important advantages: native 3D microtumors that preserve more of the patient’s original tumor architecture and microenvironment, measurement of both tumor-cell killing and growth suppression so a broader range of chemotherapies and targeted therapies can be evaluated, and a clinically practical turnaround of about 7–10 days. There are now a few other labs, but you might want to make sure their test reflects the native tumor biology, can assess with a broad range of chemotherapies and targeted therapies, and has a reasonable turn around time.

In Summary

Even if your tumor carries a specific mutation, this does not guarantee that a genome-driven targeted therapy is going to work. In other words, the premise of precision medicine is not as accurate and effective as the naming suggests. That’s where functional profiling can provide you with more certainty as it is the only approach to test how live tumor tissues respond to various treatment options to make better informed treatment decisions.

References

1. Flaherty KT et al. Molecular landscape and actionable alterations in a genomically guided cancer clinical trial: National Cancer Institute Molecular Analysis for Therapy Choice (NCI-MATCH). J Clin Oncol. 2020;38(33):3883-3894.

2. Zerdes I, et al. Comprehensive genome profiling for treatment decisions in patients with metastatic tumors: real-world evidence meta-analysis and registry data implementation. J Natl Cancer Inst. 2025;117(6):1117- 1124.

3. ENHERTU® prescribing information. Daiichi Sankyo, Inc. Basking Ridge, NJ; 2019.

4. BRAFTOVI® prescribing information. Array BioPharma Inc. Boulder, CO.

5. TAGRISSO® prescribing information. AstraZeneca Pharmaceuticals LP. Wilmington, DE.

6. PIQRAY® prescribing information. Novartis Pharmaceuticals Corp. East Hanover NJ.

7. LYNPARZA® prescribing information. AstraZeneca Pharmaceuticals LP . Wilmington, DE.

8. Fulton-Ward T, et al. The impact of genomic context on outcomes of solid cancer patients treated with genotype-matched targeted therapies: a comprehensive review. Ann Oncol. 2023;34(12):1113-1130.

9. Ranjan T et al. Cancer stem cell assay-guided chemotherapy improves survival of patients with recurrent glioblastoma. Cell Rep Med. 2023;4(5):1025.

10. Herzog TJ et al. ChemoID-guided therapy improves objective response rate in recurrent platinum-resistant ovarian cancer randomized clinical trial. NPJ Precis Oncol. 2025;9(1).

11. Volm M, Efferth T. Prediction of Cancer Drug Resistance and implications for Personalized Medicine. Front Oncol, 2015;5:282.