Actionable Alterations and ctDNA Testing May Refine Precision Strategies in Breast and Colorectal Cancers

Comprehensive tumor profiling and circulating tumor DNA (ctDNA) analysis are increasingly shaping precision oncology strategies, offering insights into tumor biology and opportunities for targeted therapy. Findings from an American Association for Cancer Research (AACR) Annual Meeting abstract demonstrate a high prevalence of actionable alterations (AAs) in breast cancer (BC) and colorectal cancer (CRC), while highlighting the complementary role of ctDNA testing in disease monitoring and treatment decision-making.¹

Widespread Detection of Actionable Alterations

Tumor molecular profiling enables the identification of genomic alterations that may guide targeted therapy selection and improve outcomes. In the AACR study, investigators evaluated 88 patients (42 with BC, 46 with CRC) who underwent whole transcriptome and whole exome sequencing alongside ctDNA testing.¹

AAs were identified in nearly all patients, including 100% of those with CRC and 97.6% of those with BC. Notably, 52.3% of patients had alterations linked to FDA-approved therapies, underscoring the clinical relevance of genomic testing in routine oncology practice.¹ These results are consistent with previous studies that showed that a major part of the solid tumors can be identified as targetable mutations with molecular profiling on a large scale.²

Across disease stages, AAs remained highly prevalent. All stage 3 and 4 tumors, as well as most stage 1 tumors (85.7%), harbored at least 1 actionable mutation, suggesting that even early-stage disease may benefit from precision-guided strategies.¹

Targetable Alterations and Therapeutic Implications

The study further identified key genomic alterations with therapeutic implications. In hormone receptor–positive (HR+)/HER2-negative BC, over half of the samples (54.2%) contained AAs associated with approved therapies.¹ Among these, PIK3CA mutations were commonly observed and are clinically actionable with agents such as alpelisib (Piqray; Novartis).³

In CRC, PIK3CA mutations were identified in 26.5% of stage 2 and 3 tumors.¹ These alterations have been associated with improved survival in patients treated with aspirin, illustrating how molecular findings can influence both targeted and supportive therapeutic strategies.⁴

When stratified by stage, AAs associated with approved therapies were identified in 81.8% of stages 1 to 2 CRC and 65.7% of stages 3 to 4 CRC.¹ In BC, rates were lower but consistent across stages (31.3% in stages 1-2 vs 36.0% in stages 3-4).¹ These differences highlight disease-specific genomic landscapes and reinforce the importance of individualized treatment approaches.

ctDNA Testing and Its Role in Clinical Decision-Making

ctDNA testing offers a minimally invasive method for assessing tumor burden, detecting minimal residual disease (MRD), and monitoring treatment response over time.⁵ In this study, however, there was no direct association observed between the presence of AAs and ctDNA detection.¹

Interestingly, AAs linked to approved therapies were more frequently identified in ctDNA-negative samples compared with ctDNA-positive samples in both BC (46.2% vs 27.6%) and CRC (82.4% vs 62.1%).¹ These findings suggest that ctDNA status alone may not fully capture the underlying genomic landscape and should not replace tissue-based profiling.

Implications for Oncology Practice

The AACR findings emphasize the complementary roles of tumor genomic profiling and ctDNA analysis in precision oncology. While tissue-based sequencing identifies actionable mutations that inform therapy selection, ctDNA testing offers dynamic, real-time insights into disease status and evolution.¹

For pharmacists and oncology care teams, these results highlight the importance of incorporating both diagnostic approaches into clinical workflows. As targeted therapies continue to expand and biomarker-driven care becomes standard, integrating genomic and liquid biopsy data may improve treatment selection, optimize monitoring strategies, and ultimately enhance patient outcomes.

REFERENCES

1. Basu G, Johnson N, Deem A, et al. Investigating the value of testing for actionable alterations and circulating tumor DNA in breast and colorectal cancers. Presented at: American Association for Cancer Research Annual Meeting; April 20, 2026; San Diego, CA. Abstract 3243. Accessed April 22, 2026. https://www.abstractsonline.com/pp8/#!/21436/presentation/7898

2. Malone ER, Oliva M, Sabatini PJB, Stockley TL, Siu LL. Molecular profiling for precision cancer therapies. Genome Med. 2020;12(1):8. doi:10.1186/s13073-019-0703-1

3. André F, Ciruelos E, Rubovszky G, et al. Alpelisib for PIK3CA-mutated, hormone receptor-positive advanced breast cancer. N Engl J Med. 2019;380(20):1929-1940. doi:10.1056/NEJMoa1813904

4. Liao X, Lochhead P, Nishihara R, et al. Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival. N Engl J Med. 2012;367(17):1596-1606. doi:10.1056/NEJMoa1207756

5. Wan JCM, Massie C, Garcia-Corbacho J, et al. Liquid biopsies come of age: towards implementation of circulating tumour DNA. Nat Rev Cancer. 2017;17(4):223-238. doi:10.1038/nrc.2017.7