Melanoma blood test

Blood test that determines BRAF status

ACCO members may be puzzled by the recent media' attention regarding a “melanoma blood test”.

What is it ? What is it’s role ?

Around half of metastatic melanoma patients have the BRAF mutation. Patients with inoperable metastatic melanoma who carry the BRAF mutation can be treated with targeted chemotherapy. Up until recently one needed to obtain a sample of metastatic melanoma tissue to determine BRAF status if the primary tumor tissue is not available. 

Media attention concerns a “melanoma blood test” that detects the presence or absence of BRAF mutation.  The key research here is Panka et al. (Abstract below) 1.

Metastatic melanoma patients who are BRAF positive can be offered the combination BRAF inhibitor / MEK chemotherapy. Most commonly a combination of Dabrafenib with Trametinib is commenced. See below the abstract of the key paper published in New England Journal by Robert et al 2.

Unfortunately, the media in November 2016 has completely misrepresented the situation. Let’s pick through it:

       An Australian breakthrough!  - No, actually a Boston development.

       Brand new discovery! – No, actually published in 2014. What is new is that the Austin Hospital now have access to the blood test.

       A major achievement by the Austin (Olivia Newton-John) Cancer Centre ! – Hardly. They just bought the ability and equipment to do the blood test.

       Will save lives? – Possibly. The blood test makes BRAF status detectable earlier. Whether this matters is unknown because it has not yet been shown whether commencing BRAF therapy early improves overall survival.  Nevertheless, there are anecdotes of folk doing badly having a dramatic improvement. We also know that with most of our patients, the BRAF / MEK response is often initially favourable, then wears off.

       Blood test can now swiftly diagnose melanoma! – Completely wrong. It does not do so. The test identifies BRAF status in patients with KNOWN metastatic melanoma, and recall that only half of patients carry the BRAF mutation.

      “Health Minister announces world first cancer diagnosis!” – No. Austin is the first Australian institution to offer the test. Beth Israel Hospital Boston has had it for several years. As has MD Anderson Hospital in Texas. And many other sites.

Reality:

The new blood test is a forward step. At times patients with metastatic melanoma do not have readily accessible metastatic tumors to obtain a tissue biopsy. For example, a patient with only brain metastases would require a brain biopsy to determine BRAF status. This blood test can quickly determine the mutation status, obviating the need for invasive procedures.

We are getting patients coming in now wanting the “melanoma blood test”. I hope the above will allow ACCO members to advise their patients that for diagnosis of primary cutaneous melanoma the method remains skin checks with dermoscopy and local excision of the entire lesion with a narrow margin for histology of suspicious lesions.

1.       Panka, D. J., et al. (2014). "Clinical utility of a blood-based BRAF(V600E) mutation assay in melanoma." Mol Cancer Ther 13(12): 3210-3218.

              BRAF inhibitors (BRAFi) have led to clinical benefit in patients with melanoma. The development of a blood-based assay to detect and quantify BRAF levels in these patients has diagnostic, prognostic, and predictive capabilities that could guide treatment decisions. Blood BRAF(V600E) detection and quantification were performed on samples from 128 patients with stage II (19), III (67), and IV (42) melanoma. Tissue BRAF analysis was performed in all patients with stage IV disease and in selected patients with stage II and III disease. Clinical outcomes were correlated to initial BRAF levels as well as BRAF level dynamics. Serial analysis was performed on 17 stage IV melanoma patients treated with BRAFi and compared with tumor measurements by RECIST. The assay was highly sensitive (96%) and specific (95%) in the stage IV setting, using a blood level of 4.8 pg as "positive." BRAF levels typically decreased following BRAFi. A subset of these patients (5) had an increase in BRAF(V600E) values 42 to 112 days before clinical or radiographic disease progression (PD). From 86 patients with resected, stage II or III melanoma, 39 had evidence of disease relapse (45.3%). Furthermore, BRAF mutation in the blood after surgical resection in these patients was not associated with a difference in relapse risk, although tissue BRAF status was only available for a subset of patients. In summary, we have developed a highly sensitive and specific, blood-based assay to detect BRAF(V600) mutation in patients with melanoma.

2.       Robert, C., et al. (2015). "Improved overall survival in melanoma with combined dabrafenib and trametinib." N Engl J Med 372(1): 30-39.

              BACKGROUND: The BRAF inhibitors vemurafenib and dabrafenib have shown efficacy as monotherapies in patients with previously untreated metastatic melanoma with BRAF V600E or V600K mutations. Combining dabrafenib and the MEK inhibitor trametinib, as compared with dabrafenib alone, enhanced antitumor activity in this population of patients. METHODS: In this open-label, phase 3 trial, we randomly assigned 704 patients with metastatic melanoma with a BRAF V600 mutation to receive either a combination of dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) or vemurafenib (960 mg twice daily) orally as first-line therapy. The primary end point was overall survival. RESULTS: At the preplanned interim overall survival analysis, which was performed after 77% of the total number of expected events occurred, the overall survival rate at 12 months was 72% (95% confidence interval [CI], 67 to 77) in the combination-therapy group and 65% (95% CI, 59 to 70) in the vemurafenib group (hazard ratio for death in the combination-therapy group, 0.69; 95% CI, 0.53 to 0.89; P=0.005). The prespecified interim stopping boundary was crossed, and the study was stopped for efficacy in July 2014. Median progression-free survival was 11.4 months in the combination-therapy group and 7.3 months in the vemurafenib group (hazard ratio, 0.56; 95% CI, 0.46 to 0.69; P<0.001). The objective response rate was 64% in the combination-therapy group and 51% in the vemurafenib group (P<0.001). Rates of severe adverse events and study-drug discontinuations were similar in the two groups. Cutaneous squamous-cell carcinoma and keratoacanthoma occurred in 1% of patients in the combination-therapy group and 18% of those in the vemurafenib group. CONCLUSIONS: Dabrafenib plus trametinib, as compared with vemurafenib monotherapy, significantly improved overall survival in previously untreated patients with metastatic melanoma with BRAF V600E or V600K mutations, without increased overall toxicity. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT01597908.).

Prof. Anthony J. Dixon  - Geelong, ACCO Director
Prof. Howard K. Steinman – Texas, ACCO Director
Dr. Stuart Anderson - Maffra, ACCO Chair