Publication

Article

Oncology Live®
Vol. 25/No. 10
Volume 25
Issue 10

Precision Cancer Medicine: The Past, Present, and Future

Maurie Markman, MD

Maurie Markman, MD

It may be somewhat difficult for oncologists to remember a time before the introduction of the concept of molecularly defined cancer therapeutics. This was the era prior to the landmark studies revealing that targeting a negative prognostic biological marker such as HER2 overexpression could favorably affect breast cancer survival,1 the demonstration that imatinib (Gleevec) would revolutionize the care of patients with chronic myelocytic leukemia (CML),2 the documentation of the presence (or absence) of specific somatic mutations in EGFR that would help define standard-ofcare management of metastatic non–small cell lung cancer,3 and the delivery of PARP inhibitors in the maintenance setting that would be shown to rather dramatically extend progression-free survival in patients with epithelial ovarian cancer possessing either a germline or tumor-only BRCA1 or BRCA2 mutation.4

What must feel to some like true ancient history, it was only 14 years ago that Von Hoff et al, employing what today would surely be considered rather primitive technology, published their landmark study demonstrating the potential clinical utility associated with targeting specific documented molecular events within individual cancers as a therapeutic strategy,5 a process that became widely known as precision cancer medicine. Other centers subsequently published their own tumor board experiences in the selection of specific antineoplastic agents based on potentially clinically relevant targets found in individual patients’ cancers.6

Since then, there have been a number of assumptions that have been proven to be incorrect, resulting in expensive mistakes in drug development and large numbers of participants being enrolled in unsuccessful clinical trials. A striking example of this experience was the failed efforts to treat cancers with EGFR inhibitors solely on the basis of the observation that the tumor type overexpressed the growth factor receptor.7 The discovery of the utility of these inhibitors in the presence of EGFR mutations (rather than mere overexpression) proved to be a major event in the management of lung cancer.8

This era also saw the publication of rather data-free opinion pieces that challenged the basic premise of the process of precision cancer medicine.9 In addition, studies were reported suggesting the negative results of clinical trials revealed the lack of utility of this approach, when in fact the efforts should have more appropriately been viewed as excellent examples of the actual value of the precision medicine process itself by permitting a reasonable conclusion that either the target in question was not relevant (“not a driver of tumor growth”), or that the drugs being examined simply failed to effectively inhibit the suggested target, or that both conclusions explaining the failure to reveal tumor response were possibly valid.10

Over the past decade, we have witnessed an acceleration in the number of novel antineoplastic agents approved for noninvestigative use whose clinical activity is directly linked to the presence of specific molecular abnormalities either only within the tumor itself or potentially also in the germline. Perhaps one of the most exciting recent developments has been the unprecedented favorable regulatory decisions for novel precision medicine–based antineoplastic agents to achieve tumor agnostic approval, meaning the delivery of the drug is based on the presence of a well-defined molecular target rather than the documentation of a particular histologic cell type within a specific organ.11

These striking advances in molecular- based therapeutics have been accompanied by impressive developments in the technology employed to document the presence of relevant molecular targets. Costs of sequencing and the time required to obtain meaningful results have dramatically decreased over the years. On the horizon are more cost-effective liquid biopsy tests that will permit the routine molecular monitoring of blood for the presence of disease recurrence or resistance mutations that can subsequently be treated with specific targeted antineoplastic agents.

Not surprisingly, there remains considerable debate regarding the optimal testing platform as multiple commercial and academic laboratories continue to rapidly move the field of molecular diagnostics forward. One can only imagine how efforts in artificial intelligence may someday transform this entire diagnostic arena.

To be clear, although the process of exploration of relevant molecular targets and discovery of corresponding pharmaceutical agents developed to effectively inhibit tumor growth have made considerable progress, the field realistically remains in its infancy. There are unfortunately only a modest number of truly major success stories of the degree observed with imatinib in CML or of PARP inhibitors as first-line maintenance of BRCA mutation–positive epithelial ovarian cancer.2,4

One proposed alternative precision cancer medicine strategy that might be employed along with, or in certain settings in place of, molecular-based therapy is the use of in vitro functional tests examining specific drugs/ combination regimens against individual patient’s cancers.12

Innovative clinical trial strategies have been proposed to more efficiently explore novel drugs in uncommon/rare molecularly defined subsets (eg, the TRIUMPH trial for patients with recurrent or metastatic head and neck squamous cell carcinoma).13

In conclusion, today precision cancer medicine is a foundational component of oncologic care and research and should be anticipated to rapidly change with advances in our understanding of cancer biology as well as future developments in molecular diagnostics.

Maurie Markman, MD, is president of Medicine & Science at City of Hope Atlanta, Chicago, and Phoenix.

References

  1. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344(11):783-792. doi:10.1056/NEJM200103153441101
  2. O’Brien SG, Guilhot F, Larson RA, et al; IRIS Investigators. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003;348(11):994-1004. doi:10.1056/NEJMoa022457
  3. Rosell R, Carcereny E, Gervais R, et al; Spanish Lung Cancer Group in collaboration with Groupe Français de Pneumo-Cancérologie and Associazione Italiana Oncologia Toracica. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012;13(3):239-246. doi:10.1016/S1470-2045(11)70393-X
  4. Moore K, Colombo N, Scambia G, et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2018;379(26):2495-2505. doi:10.1056/NEJMoa1810858
  5. Von Hoff DD, Stephenson Jr JJ, Rosen P, et al. Pilot study using molecular profiling of patients’ tumors to find potential targets and select treatments for their refractory cancers. J Clin Oncol. 2010;28(33):4877- 4883. doi:10.1200/JCO.2009.26.5983
  6. Schwaederle M, Parker BA, Schwab RB, et al. Molecular tumor board: the University of California- San Diego Moores Cancer Center experience. Oncologist. 2014;19(6):631-636. doi:10.1634/ theoncologist.2013-0405
  7. Vergote IB, Jimeno A, Joly F, et al. Randomized phase III study of erlotinib versus observation in patients with no evidence of disease progression after first-line platin-based chemotherapy for ovarian carcinoma: a European Organisation for Research and Treatment of Cancer- Gynaecological Cancer Group, and Gynecologic Cancer Intergroup Study. J Clin Oncol. 2014;32(4):320-326. doi:10.1200/ JCO.2013.50.5669
  8. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350(21):2129- 2139. doi:10.1056/NEJMoa040938
  9. Prasad V. Perspective: the precision-oncology illusion. Nature. 2016;537(7619):S63. doi:10.1038/537S63a
  10. Le Tourneau C, Delord JP, Goncalves A, et al; SHIVA Investigators. Molecularly targeted therapy based on tumour molecular profiling versus conventional therapy for advanced cancer (SHIVA): a multicentre, open-label, proof-of-concept, randomised, controlled phase 2 trial. Lancet Oncol. 2015;16(13):1324- 1334. doi:10.1016/S1470-2045(15)00188-6
  11. Gouda MA, Nelson BE, Buschhorn L, Wahida A, Subbiah V. Tumor-agnostic precision medicine from the AACR GENIE database: clinical implications. Clin Cancer Res. 2023;29(15):2753-2760. doi:10.1158/1078-0432.CCR-23-0090
  12. Dolgin E. The future of precision cancer therapy might be to try everything. Nature. 2024;626(7999):470-473. doi:10.1038/d41586-024-00392-2
  13. Keam B, Hong MH, Shin SH, et al; KCSG TRIUMPH Investigators. Personalized biomarker-based umbrella trial for patients with recurrent or metastatic head and neck squamous cell carcinoma: KCSG HN 15-16 TRIUMPH trial. J Clin Oncol. 2024;42(5):505-517. doi:10.1200/JCO.22.02786
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