Progress in Precision Oncology: AACR Cancer Progress Report 2023

Liquid biopsy, molecular profiling, and other recent advances from the AACR Cancer Progress Report 2023

Michael Schubert, PhD

Michael Schubert, PhD, is a veteran science and medicine communicator. He holds graduate degrees in biochemistry and molecular biology with a research focus on chromatin structure and function and has written on subjects from subspeciality pathology to fictional science. In addition to writing and editing, he is co-director of the Digital Communications Fellowship in Pathology and professor of professional practice in academic writing at ThinkSpace Education, the University of Chichester.

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Published:Nov 01, 2023
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Data from the recent American Association for Cancer Research (AACR) Cancer Progress Report 2023 illustrates a growing victory against the disease, with overall mortality down 33 percent over the last three decades—equating to nearly four million deaths averted in the US alone.1 Despite this progress, an estimated 2 million new cases and more than 600,000 deaths are expected in the US in 2023,2 highlighting the importance of faster, more accurate, and less invasive screening and diagnosis. To that end, the report emphasizes expanding both early cancer detection and accurate molecular diagnosis and treatment selection.

Reducing invasive testing

A key area for advancement in cancer screening and diagnosis is liquid biopsy, which examines body fluid samples for signs of cancer—most often circulating tumor cells (CTCs) or circulating tumor DNA (ctDNA). Liquid biopsy is an increasing presence in research and the scientific literature (Figure 1), as well as the clinic, where it has applications from minimal residual disease monitoring3 to pediatric solid tumor diagnosis.4

Graphic that shows the number of publications published on the topic of liquid biopsy from 2013 to 2022.
Figure 1. Data were obtained by searching the term “liquid biopsy” in PubMed for each year from January 1 to December 31. The Species filter in PubMed was applied and set to “Humans.” No other limitations were placed on the data.
Pubmed, Today's Clinical Lab

The technique is not without limitations. Not all cancers have detectable circulating biomarkers, and even those that do are often unreliable or fall below the limits of detection, especially in the early stages of disease.5 Nonetheless, ongoing efforts to establish standards and drive improvements6 mean that liquid biopsy offers promise for minimally invasive cancer screening.

This includes multi-cancer early detection (MCED), which involves testing a single sample for a range of cancer biomarkers. Not only can this approach help remove certain barriers to screening (such as patients’ reluctance to undergo invasive testing),7 but it can also allow doctors to investigate nonspecific symptoms without the need for multiple tests.

A tissue-agnostic approach

Liquid biopsy, including MCED, offers significant benefit to patients with cancers of unknown primary origin. By providing minimally invasive access to tumor cells and genetic material, such testing can help identify the tissue of origin, increasing diagnostic accuracy and guiding treatment decisions.8 Although knowledge of a tumor’s primary site can provide vital information,9 cancer treatment no longer relies solely on anatomical context and histological analysis. Instead, patients are increasingly prescribed treatment based on the molecular features of their disease. This approach has led to new concepts like “basket trials” (in which targeted treatments are evaluated in multiple diseases that share actionable mutations)10 and even combination therapies that either target multiple mutations11 or pair targeted therapies with other treatments.12

Classifying cancers according to their molecular profiles can open up new therapeutic avenues. The MyPathway basket study found that targeted therapy delivered clinically meaningful outcomes in patients with actionable HER2, BRAF, EGFR, or Hedgehog pathway alterations—even if the treatment those patients received was not labeled for use in their disease.13 In its report, the AACR highlights 14 new targeted treatment approvals between August 1, 2022, and July 31, 2023, five of which include companion diagnostics to identify patients most likely to respond (Table 1).14

TreatmentTargetFunctionCancer Type

Companion Diagnostic?

adagrasib
KRAS, G12C
Cell signaling inhibitorsSome lung cancersYes
dabrafenib + trametinib
BRAF, V600E
Cell signaling inhibitors
Some gliomas
No
elacestrant
ESR1
Estrogen receptor antagonist
Some breast cancers
No
fam-trastuzumab deruxtecan-nxki
ERBB2
Antibody-drug conjugate
Some lung cancers
Yes
futibatinib
FGFR2

Cell signaling inhibitor

Some bile duct cancers
No
mirvetuximab soravtansine-gynx
FRα
Antibody-drug conjugate
Some ovarian cancers
Yes
olutasidenib
IDH1
Epigenome modifier
Some leukemias
Yes
pemigatinib
FGFR2

Cell signaling inhibitor

Some blood cancers
No

pirtobrutinib

BTK, C481S

Cell signaling inhibitors

Some lymphomas
No

quizartinib

FLT3, ITD


Cell signaling inhibitors


Some leukemias
Yes
selpercatinib
RET

Cell signaling inhibitor

Some solid tumors
No
talazoparib
BRCA1/2

DNA repair inhibitor

Some prostate cancers
No

tucatinib + trastuzumab
ERBB2
Cell signaling inhibitor
Some colorectal cancers
No
zanubrutinib
BTK

Cell signaling inhibitor

Some lymphomas
No
Table 1. New FDA targeted treatment approvals (August 1, 2022–July 31, 2023). Some data adapted from AACR (2023).14

As precision oncology has progressed, the advantages of liquid biopsy have become clear: it can be performed when traditional tissue biopsy is impossible or the sample is insufficient,15 it can provide a snapshot of intratumoral heterogeneity without the need for multiple samples,16 and because the material can be analyzed using a variety of sequencing technologies,17 it can reveal actionable mutations within the tumor’s molecular profile, potentially increasing patients’ access to targeted therapies. Liquid biopsy can also provide a minimally invasive view of treatment response, enabling rapid pivots if a chosen treatment is ineffective or the cancer develops resistance.18

Clinical challenges to overcome

Although the recent AACR report emphasizes the promise of liquid biopsy for multi-cancer and tissue-agnostic detection, the technique remains in its infancy. For instance, it’s still uncertain how early or accurately MCED tests can reveal the presence of disease.19 Conversely, highly sensitive tests may yield positive results that can’t be verified by other means, raising questions about whether the findings reflect very early-stage cancers or true false positives.20 So far, patients with positive MCED and negative clinical and imaging results demonstrate a low likelihood of developing cancer in the four years following MCED testing.21

Overall, our understanding of cancer—and therefore, our ability to detect, diagnose, and treat it—is rapidly growing with the advent of new technologies in liquid biopsy and precision oncology. Despite these advances, cancer remains a threat until these technologies reach the clinic and until stronger public health policies ensure universal access to early detection, accurate diagnosis, and appropriate treatment. Until then, clinical laboratory professionals play a vital role not only in supporting current patients but in the research and advocacy that can save lives.

References:

  1. AACR Cancer Progress Report: Executive Summary. American Association for Cancer Research. September 13, 2023. https://cancerprogressreport.aacr.org/progress/cpr23-contents/cpr23-executive-summary.
  2. Siegel RL et al. Cancer statistics, 2023. CA Cancer J Clin. 2023;73(1):17–48. doi:10.3322/caac.21763.
  3. Stergiopoulou D et al. Comprehensive liquid biopsy analysis as a tool for the early detection of minimal residual disease in breast cancer. Sci Rep. 2023;13(1):1258. doi:10.1038/s41598-022-25400-1.
  4. Christodoulou E et al. Combined low-pass whole genome and targeted sequencing in liquid biopsies for pediatric solid tumors. NPJ Precis Oncol. 2023;7(1):21. doi:10.1038/s41698-023-00357-0.
  5. S Connal et al. Liquid biopsies: the future of cancer early detection. J Transl Med. 2023;21(1):118. doi:10.1186/s12967-023-03960-8.
  6. Doubeni CA et al. Development and evaluation of safety and effectiveness of novel cancer screening tests for routine clinical use with applications to multicancer detection technologies. Cancer. 2022;128 Suppl 4:883–891. doi:10.1002/cncr.33954.
  7. Bynum SA et al. Unwillingness to participate in colorectal cancer screening: examining fears, attitudes, and medical mistrust in an ethnically diverse sample of adults 50 years and older. Am J Health Promot. 2012;26(5):295–300. doi:10.4278/ajhp.110113-QUAN-20.
  8. Posner A et al. A comparison of DNA sequencing and gene expression profiling to assist tissue of origin diagnosis in cancer of unknown primary. J Pathol. 2023;259(1):81–92. doi:10.1002/path.6022.
  9. Schneider G et al. Tissue-specific tumorigenesis: context matters. Nat Rev Cancer. 2017;17(4):239–253. doi:10.1038/nrc.2017.5.
  10. Park JJH et al. An overview of precision oncology basket and umbrella trials for clinicians. CA Cancer J Clin. 2020;70(2):125–137. doi:10.3322/caac.21600.
  11. Hong D, Chintala L. Combining targeted therapies. In: Kurzrock R, Markman M, eds. Targeted Cancer Therapy. Totowa, NJ, USA: Humana; 2008:361–381.
  12. Guo C-X et al. Combined targeted therapy and immunotherapy for cancer treatment. World J Clin Cases. 2021;9(26):7643–7652. doi:10.12998/wjcc.v9.i26.7643.
  13. Hainsworth JD et al. Targeted therapy for advanced solid tumors on the basis of molecular profiles: results from MyPathway, an open-label, phase IIa multiple basket study. J Clin Oncol. 2018;36(6):536–542. doi:10.1200/JCO.2017.75.3780.
  14. AACR Cancer Progress Report: Advancing the Frontiers of Cancer Science and Medicine. American Association for Cancer Research. September 13, 2023. https://cancerprogressreport.aacr.org/progress/cpr23-contents/cpr23-advancing-the-frontiers-of-cancer-science-and-medicine/
  15. Palmero R et al. Biomarker discovery and outcomes for comprehensive cell-free circulating tumor DNA versus standard-of-care tissue testing in advanced non-small-cell lung cancer. JCO Precis Oncol. 2021;5:93–102. doi:10.1200/PO.20.00241.
  16. Gilson P et al. Deciphering tumour heterogeneity: from tissue to liquid biopsy. Cancers (Basel). 2022;14(6):1384. doi:10.3390/cancers14061384.
  17. Brockley LJ et al. Sequence-based platforms for discovering biomarkers in liquid biopsy of non-small-cell lung cancer. Cancers (Basel). 2023:15(8):2275. doi:10.3390/cancers15082275.
  18. Kilgour E et al. Liquid biopsy-based biomarkers of treatment response and resistance. Cancer Cell. 2020;37(4):485–495. doi:10.1016/j.ccell.2020.03.012.
  19. Doubeni CA, Castle PE. Multicancer early detection: a promise yet to be proven. Am Fam Physician. 2023;107(3):224–225A.
  20. Nadauld L, Goldman DP. Considerations in the implementation of multicancer early detection tests. Future Oncol. 2022;18(28):3119–3124. doi:10.2217/fon-2022-0120.
  21. Lennon AM et al. Outcomes in participants with a false positive multi-cancer early detection (MCED) test: results from >4 years follow-up from DETECT-A, the first large, prospective, interventional MCED study. J Clin Oncol. 2023;41(16):3039. doi:10.1200/JCO.2023.41.16_suppl.3039.

Michael Schubert, PhD

Michael Schubert, PhD, is a veteran science and medicine communicator. He holds graduate degrees in biochemistry and molecular biology with a research focus on chromatin structure and function and has written on subjects from subspeciality pathology to fictional science. In addition to writing and editing, he is co-director of the Digital Communications Fellowship in Pathology and professor of professional practice in academic writing at ThinkSpace Education, the University of Chichester.


Tags:

Cancer TreatmentsTherapeuticsCancer DiagnosticsBreast CancerCancer Researchliquid biopsy
Top Image:
Despite progress, an estimated 2 million new cases of cancer, and more than 600,000 deaths, are expected in the US in 2023.
iStock, elenabs