Serial Biopsies Identify Treatment Resistance and Inform Therapy Decisions in Patients with Advanced Solid Malignancies

Cancers often arise as a result of genomic instability and the evolution of neoplastic cell populations with variable types of genetic alterations.¹ Consequently, each patient’s malignancy may change and determine numerous clinical phenotypes throughout the course of the disease.¹ Relative to primary tumors, metastatic tumors tend to have an increased mutational burden and higher clonal diversity or heterogeneity.² Mechanisms of treatment resistance due to tumor heterogeneity may vary between individuals with similar biomarkers, across metastatic lesions within a patient (intermetastatic heterogeneity), or within a single lesion (intratumoral heterogeneity).^2,3 Intermetastatic and intratumoral heterogeneity can both play significant roles in response and resistance to treatment. Therefore, the expression status and quantity of molecular effector proteins along various growth, differentiation, and proliferation cascades (eg, membrane or nuclear receptors) can be dynamic and evolve during the course of treatment and tumor progression. As these molecular effectors represent classic targets of “rationally designed” anticancer therapies, biopsies of multiple lesions in the same patient at various time points are critical in providing a more extensive molecular tumor profile and informing an appropriate therapy approach via the use of targeted and/or immuno-oncology agents.² An approach using serial biopsies may be useful in identifying molecular features only detected by the use of successive biopsies and allow for the utilization of technologies and therapies that would have not been otherwise considered in given patients during their disease journey.⁴

In general, tissue biopsies have been used to establish the tumor histology at baseline.⁵ Progressive advancements in sequencing technologies such as next-generation sequencing and polymerase chain reaction—the latter for a specific set of genes or gene aberrations—have transformed broad genomic profiling to detect genomic mutations across multiple tumor types; this is certainly the case in primary tumors, and for many specific malignancies, molecular profiling is the expected norm at the time of initial diagnosis because it can help determine choice of optimal therapy(ies).⁵ Performing tissue biopsies serially to monitor for mutations and other genomic aberrations can accord significant clinical benefit by informing the management team on potential targets that could be addressed with novel anticancer therapies. However, this approach comes with limitations due to patient discontent, potential risks from serially repeated tissue biopsy, and difficulty in capturing the scope of tumor heterogeneity.^5,6

Minimally invasive blood-based liquid biopsies have emerged as an alternative to tissue sampling, allowing for serial monitoring of tumor molecular changes.⁶ A type of liquid biopsy, cell-free circulating tumor DNA (ctDNA) is a quantitative marker of tumor DNA used to detect genomic alterations, such as amplifications, fusions, insertions, deletions, and point mutations.⁵ ctDNA is detected after it has been actively shed into blood once a region of the tumor has become hypoxic, leading to cell death.⁵ ctDNA detection varies by clinical stage and tumor type, with >75% detection rate in patients with advanced colorectal, pancreatic, breast, bladder, and melanoma, compared with <50% in patients with brain and renal malignancies or those with only central nervous system metastatic deposits (irrespective of histology).⁵

Compared with tissue-based testing, ctDNA assays may be less sensitive in the detection of ctDNA due to the low shedding of ctDNA by some tumor types, the presence of at least partially intact blood-brain barrier, or in early stages of cancer.⁷ If mutations are detected in blood, treatment could be dependably changed based on the detection of resistance mutations with potential for improvement in prognosis. Conversely, if no resistance mutations are detected in blood, a tissue biopsy may be required for confirmation.⁵

Identification and assessment of tumor heterogeneity in real time is a pressing challenge, as it is becoming well-accepted that heterogeneity can affect cancer treatment selection and patient outcomes.

References

1. Min Q, Wang Y, Wu Q, et al. Genomic and epigenomic evolution of acquired resistance to combination therapy in esophageal squamous cell carcinoma. JCI Insight. 2021;6(17):e150203.
2. Li A, Keck JM, Parmar S, et al. Characterizing advanced breast cancer heterogeneity and treatment resistance through serial biopsies and comprehensive analytics. NPJ Precis Oncol. 2021;5:28.
3. Johnson BE, Creason AL, Stommel JM, et al. An omic and multidimensional spatial atlas from serial biopsies of an evolving metastatic breast cancer. Cell Reports Med. 2022;3:100525.
4. Burton KA, Mahen E, Konnick EQ, et al. Safety, feasibility, and merits of longitudinal molecular testing of multiple metastatic sites to inform mTNBC patient treatment in the intensive trial of omics in cancer. JCO Precis Oncol. 2022;6:e2100280.
5. Davis AA, McKee AE, Kibbe WA, Villaflor VM. Complexity of delivering precision medicine: opportunities and challenges. ASCO Educ Book. 2018;38:998-1007.
6. McKay RR, Kwak L, Crowdis JP, et al. Phase II multicenter study of enzalutamide in metastatic castration-resistant prostate cancer to identify mechanisms driving resistance. Clin Cancer Res. 2021;27(13):3610-3619.
7. Rolfo C, Mack P, Scagliotti GV, et al. Liquid biopsy for advanced NSCLC: a consensus statement from the International Association for the Study of Lung Cancer. J Thorax Oncol. 2021;16(10):1647-1662.