The Evolving Challenges of Targeting PI3K in Breast Cancer

Josh D. Lauring, 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 percent of breast cancers, with even higher rates in the estrogen receptor [ER]-positive and HER2-amplified subtypes,” Lauring said. “Several other PI3K pathway proteins, such as PTEN, Akt and PIK3R1 are also mutated.”

Lauring details efforts to develop breast cancer therapies by targeting the pathway.

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 (Afinitor). 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 trial) 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.

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 (Herceptin) in metastatic HER2-positive breast cancer, but trials combining HER2-targeted agents with PI3K or Akt inhibitors are underway, 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 (Ibrance) 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?

Biomarkers are essential to understanding how best to use PI3K-targeting drugs in the clinic. Many of us had assumed that mutational activation of the pathway would predict for inhibitor benefit, in the same way that EGFR mutations predict for responsiveness to EGFR kinase inhibitors in lung cancer. Mutations could then be used as predictive biomarkers to select patients who would benefit from PI3K inhibitors.

It is becoming clear, however, that while mutations in the pathway may enrich for responsiveness in some settings, they are not strictly predictive in a positive or negative way. In fact, a study by Hope Rugo and colleagues of a subset of patients from the BOLERO-2 trial of everolimus and exemestane suggested that the patients with the fewest genetic alterations in the growth factor receptor and PI3K pathways derived the most benefit from everolimus. Some researchers have developed gene expression signatures that may reflect PI3K pathway activation better than mutation alone.

These and various proteomic biomarkers are also being evaluated in ongoing preclinical and clinical studies, but much work remains to identify robust predictive biomarkers for PI3K pathway inhibitor benefit. An exploratory analysis of the recently reported FERGI trial combining the PI3K inhibitor pictilisib with fulvestrant showed a doubling of PFS with the addition of pictilisib in the subset of patients whose tumors expressed both the estrogen and progesterone receptors [PR]. Whether combined ER/PR positivity will identify a subset of patients who are particularly likely to benefit will need to be determined prospectively in future studies.