Josh D. Lauring, MD, PhD
Josh D. Lauring, MD, PhD, of Johns Hopkins Medicine, is interested in identifying the genetic changes that drive breast cancer growth, in order to determine novel therapeutic targets for drug development and ultimately improve outcomes for patients with breast cancer.
His focus includes the PI3K pathway, the most highly dysregulated cell-signaling network in breast cancer. “The PIK3CA
gene, encoding one of the major PI3K proteins, is mutated in approximately 30% of breast cancers, with even higher rates in the estrogen receptor [ER]-positive and HER2-amplified subtypes,” Lauring said in an interview with OncologyLive
. “Several other PI3K pathway proteins, such as PTEN, Akt, and PIK3R1 are also mutated.”
In this interview, Lauring discusses efforts to develop breast cancer therapies by targeting the pathway.OncLive: Which PI3K-targeting strategies are proving most promising and in which types of breast cancer?Lauring:
Currently, the only FDA-approved drug targeting the PI3K pathway for breast cancer is everolimus. This drug targets the mTOR protein, which is a major downstream target of the PI3K pathway. Everolimus has been most extensively studied in ER–positive breast cancer, where it provided a large progression-free survival [PFS] benefit when added to the aromatase inhibitor exemestane (BOLERO-2 trial1
) or tamoxifen (TAMRAD trial2
) in women whose cancer had progressed after initial hormonal therapy.
Studies using PI3K inhibitors or Akt inhibitors, which target the pathway above the level of mTOR, are mostly still ongoing, often in combination with hormonal therapies. The PI3K inhibitor pictilisib provided a modest but nonsignificant PFS benefit when combined with fulvestrant in women with aromatase inhibitor-resistant ER-positive breast cancer in the recently reported FERGI phase II trial, however.3
Accumulating evidence points to PIK3CA
mutation as a biomarker that predicts less responsiveness to HER2-targeting drugs in HER2-positive breast cancer, so there is great interest in determining whether adding PI3K pathway inhibitors can improve responses to HER2-targeted therapies. Everolimus had only a modest 1-month PFS benefit when combined with trastuzumab in metastatic HER2-positive breast cancer, but trials combining HER2-targeted agents with PI3K or Akt inhibitors are under way, and some promising responses have been seen in early-phase trials. Thus far, we have not seen evidence of robust activity of single-agent PI3K-Akt-mTOR inhibitors against triple-negative breast cancer, but this may require combining these drugs with chemotherapy, which is being studied.Are these agents likely to be most effective in combination with other drugs and, if so, what are the most rational combinations?
Much research has shown that the PI3K pathway participates in complex crosstalk with other important signaling pathways in cells and that PI3K signaling involves regulatory feedback loops. Blockade of PI3K can lead to feedback activation of growth factor receptors such as IGF1R, EGFR, HER2, and HER3. Sustained signaling from these receptors can bypass PI3K blockade by activating alternative pathways such as the MAPK pathway.
Mutations in MAPK pathway genes such as KRAS
can also lead to resistance to PI3K inhibitors, and researchers have shown that co-targeting PI3K and MAPK can overcome such resistance. This approach is under study clinically, but it has been a challenge to inhibit both of these major pathways in patients without undue toxicity.
Additional trials are combining various kinds of PI3K inhibitors with drugs targeting upstream growth factor receptors, such as HER2, or the estrogen receptor. Because PIK3CA
mutations are highly enriched in ER-positive and HER2-positive breast cancer, and because these signaling pathways involve PI3K, such approaches are rational.
Using a less biased approach, Jeffrey A. Engelman’s group [at Massachusetts General Hospital] recently used a combinatorial drug screen to identify synergy between PI3K inhibitors and Cdk4/6 inhibitors in PI3K inhibitor–resistant, PIK3CA
-mutant breast cancer cells. The Cdk4/6 inhibitor palbociclib has already shown very promising PFS benefit in ER-positive breast cancer combined with letrozole [its approved FDA indication], and studies of another Cdk4/6 inhibitor LEE001 are ongoing, so there will likely be interest in combining these drugs with PI3K pathway inhibitors.How significant is the development of biomarkers, and which biomarkers seem to have the most significant potential?