Development of Breast Cancer Therapy: Biomarker-Driven and Response-Guided Approaches in a Neoadjuvant Setting

Abstract

A therapeutic strategy, biomarker-driven and response-guided approach has been investigated in cancer therapy where the treatment targets heterogeneous and unstable disease. Neoadjuvant chemotherapy, for instance, is indicated based on tumor stage and subtype and its therapeutic outcomes like pathological responses are associated with the long-term prognostic probability in subgroups such as hormone receptor (HR) negative and HR-positive patients with high-grade cancers. Therefore, it would be reasonable to consider a treatment plan according to the short-time response in the stratified subgroups. It is also applicable for new therapy development, and in fact many clinical trials are under investigation in the post-neoadjuvant setting. In order to increase the therapeutic efficacy, it is recognized as necessary to incorporate biomarkers that enable us to classify conventional subtypes further including genetic mutations and epigenetic phenotypes into the planning of treatment. It is also crucial to analyze tumor biology particularly tumor evolution in the metastasis and the clonal selection by the treatment in these clinical settings.

Introduction

Breast cancers consist of heterogeneous subpopulations, and their biological properties are quite unstable (1). Therefore, cancer treatment requires multiple therapeutic modalities, often in combination, and a response-guided clinical approach especially for subgroups showing therapeutic resistance. Biomarkers representing tumor subtype and predicting therapeutic sensitivity are indispensable to identify the target subpopulation and select a corresponding treatment (2). This therapeutic strategy (i.e., a biomarker-driven and response-guided approach) is necessary for increasing therapeutic efficacy and efficiency from a pharmacoeconomical point of view in oncology practice. And it should be applicable for the development of new cancer therapies as well. To some degree, recent clinical trials have taken up this strategy in the development of new drugs (3).

Clinical practice

For identifying tumor subtypes such as luminal A-like and B-like, luminal HER2, HER2-enriched type and several triple-negative sub-subtypes, hormonal receptors (HRs), proliferation markers, HER2 amplification/overexpression and several basal markers are often used (4). Based on this, initial primary systemic therapies are recommended for each subgroup of patients, and if therapy proceeds, for instance, to neoadjuvant treatment, we are able to assess the response by measuring the size or volume of tumor on imaging, biological changes such as down-regulation of proliferation index, and the pathological responses (5). Currently the pathological complete response (pCR) and negative conversion of nodal metastasi(e)s are often used as the end point. If therapeutic resistance appears, we usually change the treatment for the patient, and if the pathological response is not favorable after surgery, we are requested to consider more intensive care for those patients.

According to a recent pooled analysis of neoadjuvant chemotherapy outcomes, although the odds ratio for pCR had no direct correlation with the hazard ratio for disease-free survival (DFS) or overall survival (OS), overall, pCR cases especially with node-negativity (ypN0) showed a significantly favorable prognosis in comparison with non-pCR cases, in stratified subgroups of HR-negative and HR-positive patients with high-grade cancers. This may imply that in patients who would have achieved pCR/ypN0, in such subgroups, a greater therapeutic impact could have been achieved both in primary tumors and in metastatic tumors from the preoperative stage, by usually 6 months of chemotherapy with or without anti-HER2 therapy (6). In contrast, in the subgroup of HR-positive patients with relatively lower grade and slow-growing phenotypes, the therapeutic impact may differ between primary tumors and metastatic tumors even in the case of pCR. The role of postoperative long-term hormone therapy needs to be taken into consideration as well. Therefore, we need to know more about the biological characteristics of primary tumors and metastatic tumors and about the changes caused by treatments.

Poly(ADP-ribose) polymerase (PARP) inhibitors are one of the current topics in breast cancer therapy development. It is noted that several PARP inhibitors currently being tested in clinical trials have various anticancer activities such as synthetic lethality and PARP-trapping activity, and have shown a high therapeutic efficacy for cases with BRCA1/2 mutations (7, 8). PARP inhibitors are going to be tested as primary therapy in single or in combination treatment in primary breast cancer patients with the BRCA1/2 mutation (3). In addition to HR, HER2, proliferation assay and histological grade, BRCA mutation may be a biomarker for PARP inhibitors.

Inhibitors of cyclin-dependent kinase (CDK) 4/6 or mammalian target of rapamycin (mTOR) inhibitors are being developed for HR-positive disease, to be administered in combination with hormonal therapy, which is compatible with the data from the Cancer Genome Atlas investigation (1). In essence, an exploratory study showed a significant reduction in Ki67 labeling index, by adding the mTOR inhibitor everolimus to the aromatase inhibitor letrozole. In addition, recent translational research has clarified the importance of analyzing any abnormality of PIK3CA and PI3K associated pathways and mTORC1 output, to predict responses (9). Hypothetically, it should be possible to consider clinical trials using mTOR inhibitors for hormone-responsive tumors with an abnormality in the PI3K-mTORC1 pathway, selectively.

We have 4 agents – 3 antibody-based therapies and 1 tyrosine kinase inhibitor – for HER2-positive diseases. HER2 status is an established selection biomarker for anti-HER2 therapy; however, it is also evident that some tumors show resistance to the treatment, particularly in the HER2-positive and HR-positive subpopulation. We need to definitely subclassify this particular disease with new biomarkers such as gene signatures and miRNA signatures. Furthermore, it seems that trastuzumab emtansine (TDM-1) is capable of reducing toxicity effects, such as neutropenia and alopecia, and therefore TDM-1–containing anti-HER2 therapy alone might be a possible option as first-line therapy (10).

It is known that triple-negative disease contains multiple sub-subtypes. Basal type tumors often carry the p53 mutation and various chromosomal mutations (1). At the present time, except for a subgroup having the BRCA mutation, chemotherapy is the only therapeutic option. It would be reasonable to investigate further any biomarkers predicting chemotherapy responses, such as multidrug transporter pumps, platinum-associated markers, variations in microtubules, alteration in intracellular metabolisms, proportion of stem-like cancer cells and immune responses in the tumor microenvironment. Because a variety of new agents are being developed for triple-negative disease, a new therapeutic strategy could be studied in various combinations to enhance those sensitivities synergistically.

Conclusion

In conclusion, a biomarker-driven and response-guided approach has been incorporated into breast cancer treatment particularly in neoadjuvant settings. Switching of drug treatments to a different class of agent may contribute to improved clinical outcomes in a resistant population. This strategy will be useful for developing new therapeutics and overcoming resistance. Postoperative adjuvant trials for non-pCR cases have also been conducted recently (3). Obviously, it is warranted that we explore the relationships between short-term response and long-term outcomes further and develop new biomarkers, not only for novel therapeutics, but also for conventional ones. Development of new imaging tools is also necessary for assessing the tumor response more quickly and more appropriately. The combination of biomarkers and imaging, well balanced, should lead to identifying a pathway for developing a novel therapy system.