Purpose
Cancers deficient in homologous recombination DNA repair, such as those with
BRCA1
or
BRCA2
(
BRCA1/2
) mutations rely on a pathway mediated by the enzyme poly(adenosine diphosphate-ribose) polymerase (PARP). PARP inhibitors (PARPi’s) have demonstrated efficacy in treating patients with germline (
g
)
BRCA1/2
, somatic (
s
)
BRCA1/2
, and
gPALB2
mutations in clinical trials. However, patients with a poor performance status (PS) and those with severe organ impairment are often excluded from clinical trials and cancer-directed treatment.
Methods
We report the cases of two patients with metastatic breast cancer who had poor PS, significant visceral disease, and
gPALB2
and
sBRCA
mutations, who derived significant clinical benefit from treatment with PARP inhibition.
Results
Patient A had germline testing demonstrating a heterozygous
PALB2
pathogenic mutation (c.3323delA) and a
BRCA2
variant of unknown significance (c.9353T>C), and tumor sequencing revealed
PALB2
(c.228_229del and c.3323del) and
ESR1
(c.1610A>C) mutations. Patient B was negative for pathologic
BRCA
mutations upon germline testing, but tumor sequencing demonstrated somatic
BRCA2
copy number loss and a
PIK3CA
mutation (c.1633G>A). Treatment with PARPi’s in these two patients with an initial PS of 3–4 and significant visceral disease resulted in prolonged clinical benefit.
Conclusion
Patients with a poor PS, such as those described here, may still have meaningful clinical responses to cancer treatments targeting oncogenic drivers. More studies evaluating PARPi’s beyond
gBRCA1/2
mutations and in sub-optimal PS would help identify patients who may benefit from these therapies.