Detecting Missed Metastases from Nominally Early-Stage Melanomas with Pump-Probe Microscopy
Abstract
The incidence and mortality statistics for melanoma are very unusual. Age-adjusted death rates for all cancers has decreased by 20% since 1975, but melanoma death rate has stayed almost constant and incidence increased 500%. Most of the incidence increase is in early-stage diagnosis and is confounded by false positives, but the more impactful issue for mortality is a fundamental weakness with the diagnostic protocols. The diagnostic gold standard begins with visual or dermoscopic inspection of suspicious lesions, followed by excision, slicing, H&E staining, and examination by a pathologist, and assign a clinical stage from 0 (noninvasive) to IV (distant metastatic disease). The 2020 U.S. estimates are 96,000 new cases of stage 0, 75,000 stage I, 8,000 stage IIA, 7,000 stage IIB/C, 10,000 stages III/IV, and about 7,000 deaths. Clinical stage does correlate with recurrence-free survival but not strongly enough. In the most extreme case, 31% of patients with stage IIc lesions (<4mm thickness and ulceration) later are diagnosed with metastatic cancer, but this nonmetastatic stage is treated only with excision, because adjuvant therapies have side effects, and most of the patients did not actually need the treatment. In fact, the problem is even broader; more patients die from melanoma after a stage I diagnosis (again, treated only by excision) than after a stage IV diagnosis (aggressive, metastatic cancer). A decade ago, figuring out which supposedly early-stage tumors had actually generated metastases would have been interesting but not very useful, because this could not have been coupled with effective treatments. Today, adjuvant therapies have made great strides (on late-stage tumors), but significant (grade 3 or 4) treatment-related adverse events occurred in 59% of the treated group. All of these trials focus on stage III or IV melanomas, hence with known metastases. Adjuvant therapies could be more effective and less toxic if applied to (nominally) early stage tumors with a high risk of being metastatic. Such early adjuvant therapy could have great benefits for disease control, reduced toxicity, and reduced health costs, but this requires a good marker for deciding which early-stage patients should go into such therapy, and existing markers have limited value. There are current clinical trials for earlier stages, such as the KEYNOTE-716 trial of pembrolizumab with resected stage IIB/IIC melanoma. However, if this were to become the standard of care, most patients would get unneeded expensive treatment (because their melanoma was nonmetastatic and cured by simple excision) with adverse effects (16.1% grade 3-4 events). A strong biomarker to identify metastatic melanoma, selecting only patients that needed treatment, would have a large impact. This proposal is centered on a novel microscopy approach (pump-probe microscopy) pioneered in the Principal Investigator’s lab. We have proven we can find incorrectly staged tumors (ones which were called stage I/II, but the patient later returned with metastatic melanoma) solely by imaging primary tumor biopsies. The challenge is that this method has been demonstrated only with thin tissue slices (5-10?micrometers). This will not give robust separation of patients by metastatic status; if only one part of a tumor generates metastases it is still dangerous, and that part need not be in a thin slice we would examine. The focus is on improving pump-probe microscopy, based on new understandings we have of the underlying physics and biology, so that thick tissue specimens can be imaged accurately. For stage IIc lesions, we believe that we can achieve a very high positive predictive value, meaning that almost all of the patients we suspect have metastatic cancer actually do, and thus should be treated with adjuvant therapy. This technology has an easy route to clinical acceptance. We are imaging biopsy specimens that doctors acquire anyway, so our method
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310887
Entities
People
- Warren S. Warren
Organizations
- Duke University
- United States Army