Invasive Breast Cancer Therapy 2017: How Well Are We Hitting the Target?

Abstract

Invasive breast cancer is a major cause of death due to cancer for American women. Progress against this disease has only been achieved through a better understanding of the cellular and molecular aspects of breast cancer. To begin with cancer of the breast is not just a loco-regional control issue. In fact, metastatic disease from invasive breast cancer is not a one-way street in that metastases metastasize and send clusters of tumor cells that migrate to other sites of the disease including back to the primary tumor. Since invasive breast cancer at diagnosis is a systemic disease, adjuvant therapy has been initially started with relatively nonselective cytotoxic agents and latter with the use of endocrine therapy. The response rate to endocrine therapy improved once we knew which cancers expressed the actionable target. Endocrine therapy was the first targeted therapy but resistance to it is common in the adjuvant setting and essentially universal in the metastatic setting. Use of everolimus and palbociclib to interdict additional signaling pathways are proof positive that newtargeted agents can overcome resistance to endocrine therapy. In the adjuvant setting the risk of a patient's having metastatic disease can be approximated by knowing the histological type of breast cancer, size of invasive component of the primary, presence or absence of lymph node or lymphovascular space involvement, the degree of histological atypia, the presence or absence or estrogen, progesterone or Her-2 neu and the patient's menopausal status. Her-2 neu positive breast cancers have been converted from the most aggressive tumors to very curable cancers in the adjuvant setting by the use of Her-2 neu specific antibodies, such as trastuzumab, to the cell surface portion of the molecule. The use of adjuvant chemotherapy has been further refined on 2 fronts. First, smaller estrogen positive node negative breast cancers benefit from tamoxifen and some benefit more or less from additional therapy with chemotherapy based on the use of predictive models. For larger node positive breast cancers, adjusting the schedule of mostly S-phase cytotoxic chemotherapy to account for tumor cell growth kinetics has improved overall survival. Unfortunately, triple negative breast cancers lack a defined actionable target. Thus, the poorer survival in this group is not understood despite the initial good response to cytotoxic chemotherapy. Refinements in the pharmacokinetics of paclitaxel by using an albumin carrier have also proved beneficial to patients with metatstatic breast cancer. Additional refinements in drug carriers or other delivery systems should help in the care of those with metastatic disease. Only by accounting for the tumor's cellular biology, growth kinetics, and the targeted drug's pharmacokinetics as well as pharmacodynamics will blocking or overcoming resistance to targeted therapy be accomplished.