According to findings published in<em> Nature Communications, </em>a blood test detecting early changes in circulating tumor DNA (ctDNA) may provide earlier indication of whether patients with hormone receptor–positive, HER2-negative breast cancer are responding to the CDK4/6 inhibitor palbociclib (Ibrance).
Nicholas Turner, MD, PhD
According to findings published inNature Communications,a blood test detecting early changes in circulating tumor DNA (ctDNA) may provide earlier indication of whether patients with hormone receptorpositive, HER2-negative breast cancer are responding to the CDK4/6 inhibitor palbociclib (Ibrance).
The test could detect a response within 2 to 3 seeks, said investigators with The Institute of Cancer Research, London, and The Royal Marsden NHS Foundation Trust. Women currently wait 2 to 3 months to find out if palbociclib treatment is working for them.
Plasma samples were collected from patients in the phase III PALOMA-3 trial and demonstrated that adding palbociclib to fulvestrant had more than double progression-free survival (PFS) in pretreated patients with HR-positive, HER2-negative breast cancer. The results showed a relative change in thePIK3CActDNA level after 15 days of treatment. This is a strong predictor for PFS (hazard ratio [HR], 3.94; log-rankP = .0013).
Nicholas Turner, MD, PhD, senior author and professor of Molecular Oncology at The Institute of Cancer Research, London, and Consultant Medical Oncologist at The Royal Marsden NHS Foundation Trust, said, “Our new study found that a blood test for cancer DNA in the first 2 weeks of treatment indicated whether the drug was likely to be effective. Having an early indication of how likely a treatment is to work might allow us to adapt treatmentswitching some patients to an alternative drug that is more likely to benefit them.”
Sequential plasma samples were collected at baseline, on day 15 of cycle 1, and at progression to assess whether early dynamic changes in ctDNA could predict PFS for patients on palbociclib. 521 patients were recruited, and 459 baseline samples were collected for DNA extraction. Out of the 455 samples analyzed for hotspot mutations in exons 9 and 20 ofPIK3CA(E542K, E545K, H1047R and H1047L), 100 cases (22.0%) were identified with aPIK3CAmutation.
While circulating DNA ratio (CDR) defined as the ratio of mutation abundance (mutant copies/ml) on treatment relative to baseline, CDR15represented the ratio of CDR on day 15 compared with baseline. Matched day 15 samples were available for 73 patients, 52 of whom received palbociclib.
There was a lowerPIK3CACDR15in patients assigned to palbociclib plus fulvestrant, in comparison to patients with fulvestrant plus placebo (P <.0001), an indication of greater reduction in ctDNA abundance. All 52 patients receiving palbociclib had a CDR15 <1, which indicated a fall in ctDNA.
According to investigators, these "data demonstrate that the antiproliferative effects of palbociclib result in a rapid fall in ctDNA levels by day 15, and thatPIK3CACDR15assessment anticipated the improved PFS seen with palbociclib in the PALOMA-3 trial.”
Patients withPIK3CACDR15above the median value of 0.034 demonstrated an inferior PFS compared to patients below the median. Patients with a high CDR15had a median PFS of 4.1 months while patients with a low, supressed CDR15(HR, 4.92; 95% CI, 1.98-12.26; log-rank testP = .0002) had a median of 11.2 months.
“It is exciting to see that using advances in diagnostic techniques, such as genetic tests for circulating tumor DNA, we may be able to more accurately define groups of patients and help us deliver the right treatment to the right patient sooner. This study provides early evidence that might help us understand sooner when a drug is successfully treating breast cancer, and if not, it can be discontinued and better approaches pursued," said Nathan Richardson, PhD, head of Molecular and Cellular Medicine at the Medical Research Council, said in a statement. The council was the main source of funding for the research.
Guidance was issued in December 2017 by the United Kingdom’s National Institute for Health and Care Excellence (NICE), supporting approval for palbociclib (Ibrance) and ribociclib (Kisqali), another CDK4/6 inhibitor, for patients with HR-positive/HER2-negative locally advanced or secondary breast cancer. Both palbociclib and ribociclib are indicated for use with an aromatase inhibitor.
Palbociclib has been approved by the FDA in the United States for treatment of patients with HR-positive, HER2-negative advanced or metastatic breast cancer in combination with an aromatase inhibitor as initial endocrine-based therapy in postmenopausal women, or fulvestrant in women with disease progression following endocrine therapy.
O’Leary B, Hrebien S, Morden JP, et al. Early circulating tumor DNA dynamics and clonal selection with palbociclib and fulvestrant for breast cancer [published online March 1, 2018].Nat Commun.doi:10.1038/s41467-018-03215-x.