Targeted Therapies For Metastatic Breast Cancer: The Next Generation

By Neil Osterweil

In 2016, an opinion piece published in the journal Nature threw cold water on the concept of precision oncology — tailoring the treatment of individual patients to the genetic characteristics of their tumors.

Vinay Prasad, MD, from the Knight Cancer Center at Oregon Health Sciences University in Portland wrote that, despite breathless anecdotes about patients for whom genomically identified targeted therapies worked spectacularly well, “most people with cancer do not benefit from the precision strategy, nor has this approach been shown to improve outcomes in controlled studies. Precision oncology remains a hypothesis in need of verification.”

For patients with metastatic breast cancer, that verification is now happening. With the advent of ever faster and ever cheaper genomic sequencing methods, better understanding of oncogenesis and mechanisms of drug resistance, and results from key clinical trials of new classes of agents, opinions about the clinical utility of multi-gene testing in breast cancer have evolved in just a few years from “it may help to inform patient selection for clinical trials” to “all cancer patients should have access to genomic testing.”

Clinical ‘actionability’

At the 2019 European Society for Medical Oncology (ESMO) Congress, breast cancer specialists discussed the rapidly evolving field of breast cancer genomics.

Monica Arnedos, MD, PhD, from the breast unit at the Gustave Roussy Cancer Center in Villejuif, France, noted that, in 2016, the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT), which ranks
genomic alterations by their clinical utility, identified the estrogen and progesterone receptors, human epidermal growth factor receptor-2 (HER2), and BRCA1 and BRCA2 germline alterations as standard targets for routine therapy, and PIK3CA, AKT1, PTEN, and ESR1 mutations plus FGFR1 amplification as investigational targets “that likely define a patient population that benefits from a targeted drug but additional data are needed.”

New additions to the scale since 2016 include:

Dr. Monica Arnedos
  • Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors in patients with mutations identified by immunohistochemistry (IHC)
  • The phosphatidylinositol 3-kinase (PIK3) inhibitor alpelisib (Piqray) for patients with HR-positive, HER2-negative cancers with PIK3CA mutations
  • The immune checkpoint inhibitor atezolizumab (Tecentriq) for patients with triple-negative breast cancers expressing programmed death ligand-1 (PD-L1)
  • Poly ADP ribose polymerase (PARP) inhibitors for patients with breast cancer and germline BRCA1/BRCA2 mutations
  • NTRK inhibitors for cancers with the ETV6-NTRK3 fusion; and
  • Anti-PD1 agents for tumors with high microsatellite instability deficient mismatch repair (MSI-H/dMMR).
Dr. Arnedos also cautioned, however, that patients have high expectations associated with multigene testing, and that “targeted therapy provided outside a clinical trial and for which there are no clinical data might be detrimental.”

New targets, new approaches

“There are very important differences between metastatic and primary breast cancers in terms of mutation burden – a much higher mutation burden in metastatic vs. primary tumors, and greater clonal diversity – that notion that metastatic disease is even more genetically heterogeneous than primary tumors – and there are changes in the mutational signature from metastasis to primary tumors,” said Jorge S. Reis-Filho, MD, PhD, from Memorial Sloan Kettering Cancer Center in New York.

For example, metastatic ER-positive, HER2-negative breast cancers are enriched for certain mutational signatures in HRD (homologous recombination deficiency) APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) and microsatellite instability. Understanding why this occurs can help investigators identify new pathways and new targets in metastatic disease, he said.

Target: HRD

Enriched HRD signatures are seen in more than 20% of metastatic breast cancers, and biallelic inactivation of HR genes are present in more than 20% of cases with HRD.

“I find this really exciting, because the whole mechanism for the repair of DNA double-strand breaks is much more than BRCA1 and BRCA2,” Dr. Reis-Filho said.

One potential approach to treating metastatic disease is with agents that inhibit DNA damage response and DNA damage signaling by targeting kinases that phosphorylate cell-cycle arrest and repair proteins.

In addition, DNA repair inhibitors could target the process whereby damaged tumor DNA attempts to repair itself.

Target: APOBEC mutagenesis

“APOBEC enzymes play a pivotal role in antibody diversification and response to viral infections, but when they express in a known physiologic manner, they cause mutations in genomic DNA,” Dr. Reis-Filho said.

Two APOBEC signatures are significantly enriched in metastatic vs. primary breast cancers, and this mutagenic activity, seen almost exclusively in ER-positive, HER2-negative tumors, may be exploitable with agents that increase genomic instability, such as PARP or ATR inhibitors.

In tumors that do not have APOBEC mutagenesis, it may be possible to inhibit either APOBEC itself or downstream mechanisms to help prevent disease progression and drug resistance.

Because APOBEC mutagenesis may occur only sporadically during tumor evolution, however, methods to define the presence of active APOBEC mutagenesis are still needed, he said.

Dr. Jorge S. Reis-Filho

Target: Chromatin remodeling genes

Another promising avenue of exploration is the targeting of chromatin remodeling genes. These genes regulate gene expression, lineage differentiation, and endocrine resistance.

“Importantly, independent investigators have demonstrated that loss-of-function mutations of these chromatin remodeling genes are associated with worse outcomes in ER-positive, HER2-negative metastatic breast cancer,” Dr. Reis-Filho said.

More than 15% of all metastatic ER-positive breast cancers have mutations in chromatin remodeling genes, and these mutations are mutually exclusive, suggesting that they are biologically relevant and that they may be effectively targeted with inhibitors of bromodomain and extraterminal motif (BET) proteins.

Finally, there is evidence to show that antibody-drug conjugates may be effective against tumors both with high and low levels of expression of HER2, Dr. Reis-Filho said.

Multiplatform approach required

“With all of these different findings and all of these different levels of evidence required if a tumor at a given time point has a particular alteration, I would contend that a multiplatform [approach] is absolutely required for the analysis of metastatic disease,” Dr. Reis-Filho said.

This approach includes analysis of tumor tissue and circulating tumor DNA for mutations, fusions genes, signatures and epigenome; analysis of RNA expression, fusions, and downstream pathways, and tumor microenvironment; multiplex immunophenotyping, and, increasingly, artificial intelligence analysis for expediting many of the analytic methods.

Dr. Arnedos disclosed honoraria from Novartis, AstraZeneca, Pfizer and Seattle Genetics; travel expenses from Roche, AstraZeneca and Novartis; clinical trial financing from PUMA, Novartis, and AstraZeneca; and research grants from Pfizer and Lilly.

Dr. Reis-Filho disclosed scientific advisory board activity with paid honoraria for Volition Rx, Paige.AI, Invicro, Roche, Genentech, and Ventana, and consulting fees from Goldman Sachs and REPARE Therapeutics.