Precision Medicine Becomes More Widespread in Breast Cancer

Francisco J. Esteva, MD, PhD

Since the discovery of the estrogen receptor (ER), precision medicine has been an integral component of treatment strategies in breast cancer, said Francisco J. Esteva, MD, PhD, adding that its application is becoming more widespread with the discovery of molecular markers beyond the current disease subtypes.

“Precision medicine has always been a big part of the way we manage our patients with breast cancer,” said Esteva. “The first targeted therapy in breast cancer was endocrine therapy. We have been measuring the ER and progesterone receptor for many years. HER2 was discovered after and became one of the major targets in breast cancer. Now, we're moving into more detailed molecular analyses.”

For example, PIK3CA has emerged as a targetable mutation in advanced hormone receptor (HR)—positive, HER2-negative disease. The mutation is found in approximately 40% of patients with HR-positive, HER2-negative disease who progress on or after endocrine-based therapy. Patients with the mutation have shown a particular amenability to PI3K inhibitors, as seen in the phase III SOLAR-1 trial.

In the study, patients with PIK3CA mutations experienced a 35% reduction in the risk of progression or death with the PI3K inhibitor alpelisib (Piqray) and fulvestrant (Faslodex) versus fulvestrant/placebo (HR, 0.65; 95% CI, 0.50-0.85; P = .001).¹ Data from the trial served as the basis for the regimen’s approval in this indication in May 2019.

In addition, immunotherapy, which has historically been an elusive approach in breast cancer, has become a viable treatment strategy in newly diagnosed, metastatic triple-negative breast cancer (TNBC) with the use of PD-L1 expression.

In the phase III IMpassion130 trial, the combination of atezolizumab (Tecentriq) and nab-paclitaxel (Abraxane) resulted in an improvement in progression-free survival (PFS) and overall survival (OS) versus nab-paclitaxel alone in the overall population. Among patients with ≥1% PD-L1 on tumor-infiltrating lymphocytes, the PFS and OS benefit was more evident.² With additional follow-up, atezolizumab maintained an OS benefit versus nab-paclitaxel (HR, 0.71; 95% CI, 0.54-0.93) in PD-L1—positive patients.³ In March 2019, the regimen received regulatory approval for the frontline treatment of patients with unresectable locally advanced or metastatic PD-L1—positive TNBC.

In an interview with OncLive, Esteva, director, Breast Medical Oncology Program, and research professor, Department of Pathology, NYU Langone Health’s Perlmutter Cancer Center, discussed how the use of precision medicine has helped improve the treatment of patients with breast cancer.

OncLive: How has precision medicine been applied in breast cancer?

Esteva: In the adjuvant setting, we use multigene assays like Oncotype DX, PAM50 (Prosigna), and MammaPrint, which help us identify patients who may not need chemotherapy. In the metastatic setting, we are now developing new assays that are more closely related to next-generation sequencing, but also target specific [aberrations], such as ER mutations, PIK3CA mutations, HER2 mutations, and so on. [It will be important to target the PIK3CA mutations] because they are a predictive marker that can help us identify patients for PI3K inhibition.

Could you discuss the data we have seen with PI3K inhibitors?

The most recent data we have are from the SOLAR-1 trial, which randomized patients with metastatic ER-positive, HER2-negative disease to receive either endocrine therapy with alpelisib or placebo. The trial included patients with PIK3CA mutations in their tumors, and those who had PIK3CA wild-type disease. Results showed a significant improvement in PFS with alpelisib in patients with PIK3CA-mutant disease.

Investigators also looked for mutations in plasma via circulating tumor DNA. These mutations correlated with improved PFS, suggesting that we might be able to use liquid biopsies to select patients for [alpelisib].

What is the state of liquid biopsies in breast cancer? How widespread is this approach?

I don't believe they're used as widely as they will be once we have specific therapies. Now, we can use liquid biopsies to gain some information in breast cancer. [For example, we can look at] ER mutations and decide which endocrine therapy we might use, whether it's fulvestrant or an aromatase inhibitor; however, that's not as well validated or developed. For HER2 mutations, there are clinical trials that we can enroll patients on. Some therapies, such as neratinib (Nerlynx) may have some impact in that space.

What have been some of the key updates with immunotherapy in breast cancer?

Immunotherapy is exploding. We’re testing immunotherapy in all solid tumors, including breast cancer, which we know is not the most immunogenic disease. More than 200 clinical trials are ongoing. For patients with metastatic breast cancer, [we’re evaluating] immunotherapy in combination with chemotherapy, targeted therapy, and radiation therapy with a variety of therapies. The majority [of approaches under investigation] are PD-1/PD-L1—based combinations, and most of them are being tested in the metastatic setting. We're also seeing some neoadjuvant and adjuvant trials that are trying to incorporate PD-1/PD-L1 therapy.

Immunotherapy has had the biggest impact in patients with newly diagnosed, metastatic PD-L1—positive TNBC. [In 2019], the FDA approved the combination of atezolizumab and nab-paclitaxel in this indication based on the results from the IMpassion130 trial, which showed a significant improvement in PFS and OS versus chemotherapy alone.

We've also seen positive data from the I-SPY 2 trial in the neoadjuvant setting with pembrolizumab (Keytruda) in combination with paclitaxel [followed by doxorubicin and cyclophosphamide]. The KEYNOTE-522 trial is evaluating the combination in a larger population. We also talked about combinations of immunotherapy with PARP inhibitors, which is an interesting approach. We saw data from the phase I/II TOPACIO/KEYNOTE-162 trial at the 2018 San Antonio Breast Cancer Symposium, which showed a high clinical response rate in patients with BRCA1/2 mutations and those without, but with some degree of homologous recombination deficiency.

Could you speak to the potential of antibody-drug conjugates?

[The furthest agent in development is] sacituzumab govitecan, which targets Trop-2. A publication in the New England Journal of Medicine showed a very high response rate and time to progression in patients with TNBC. Randomized trials in the triple-negative and ER-positive settings are ongoing. Sacituzumab govitecan is a promising therapy in TNBC. In the HER2-positive setting, we’re seeing novel therapies in addition to trastuzumab (Herceptin), pertuzumab (Perjeta), and neratinib. Newer agents, such as margetuximab, fam-trastuzumab deruxtecan-nxki (Enhertu; DS-8201), and tucatinib are also under investigation.

Despite this progress, what is the largest unmet need in breast cancer?

The biggest unmet need is the fact that 40,000 women are dying of metastatic breast cancer. Although we are prolonging survival, it remains an incurable disease with conventional therapy for the majority of patients. We still need to work to turn breast cancer into a chronic disease for the majority of patients or find a cure.

Editor’s note—–This interview took place prior to the FDA approval of alpelisib in HR-positive, HER2-negative PIK3CA-mutant, advanced or metastatic breast cancer.

References

1. André F, Ciruelos E, Rubovszky G, et al. Alpelisib for PIK3CA-mutated, hormone receptor-positive advanced breast cancer. N Eng J Med. 2019;380(20):1929-1940. doi: 10.1056/NEJMoa1813904.
2. Schmid P, Adams S, Rugo HS, et al. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med. 2018;379(22):2108-2121. doi: 10.1056/NEJMoa1809615.
3. Schmid P, Adams S, Rugo HS, et al. IMpassion130: updated overall survival (OS) from a global, randomized, double-blind, placebo-controlled, phase III study of atezolizumab (atezo) + nab-paclitaxel (nP) in previously untreated locally advanced or metastatic triple-negative breast cancer (mTNBC). J Clin Oncol. 2019;37(suppl 15; abstr 1003). doi: 10.1200/JCO.2019.37.15_suppl.1003.