Targeted Therapies for Triple-Negative Breast Cancer.

OPINION STATEMENT: Triple-negative breast cancer (TNBC) is a particularly aggressive subtype of breast cancer. TNBC is a heterogenous subtype of breast cancer that is beginning to be refined by its molecular characteristics and clinical response to a targeted therapeutic approach. Until recently the backbone of therapy against TNBC has been cytotoxic chemotherapy. However, the breast oncology community is now seeing encouraging clinical activity from molecularly targeted approaches to TNBC. Recently, we have seen 3 newly approved targeted therapies for TNBC, including the PARP inhibitors olaparib and talazoparib for germline BRCA mutation associated breast cancer (gBRCAm-BC) and most recently the checkpoint inhibitor, atezolizumab in combination with nab-paclitaxel for programmed death-ligand 1 (PD-L1+) advanced TNBC. Improved biomarkers are needed to inform better patient selection for treatment with checkpoint inhibition. Higher response rates are seen when checkpoint inhibitors are combined with chemotherapy in the first-line setting and the use of these agents at an earlier stage of the disease does show promise. Antibody-drug conjugates are generating much excitement and may allow re-examination of prior cytotoxics that failed in development due to toxicity. Tumor sequencing is identifying potential molecular targets and ongoing studies are evaluating novel small molecule agents in this field such as AKT inhibition and many others. The treatment paradigm of chemotherapy as "one size fits all" approach for management of TNBC is changing based on molecular subtyping. Soon, the term TNBC may no longer be appropriate, as this heterogenous subtype of breast cancer is further refined by its molecular characteristics and clinical response to a targeted therapeutic approach.

Emerging Novel Therapeutics in Triple-Negative Breast Cancer.

The mortality from breast cancer has steadily decreased due in part to early detection and advances in therapy. The treatment options for breast cancer vary considerably depending on the histological subtype. There are a number of very effective targeted therapies available for estrogen receptor-positive disease and for human epidermal growth factor receptor 2-positive disease. However, triple-negative breast cancer is a particularly aggressive subtype. This subtype represents an unmet need for improved therapies. TNBC is a heterogenous subtype of breast cancer that is beginning to be refined by its molecular characteristics and clinical response to a targeted therapeutic approach. Here we review the recent advances in the treatment of TNBC with emphasis on the many emerging novel targeted therapies.

Resurrection of PARP Inhibitors in Breast Cancer.

PARP enzymes are essential for DNA damage repair. Cancers with defective homologous recombination DNA repair, such has BRCA1- and BRCA2-mutated breast cancers, are targets for PARP inhibitors (PARPi) through the exploitation of synthetic lethality. A number of PARPi are currently undergoing clinical evaluation in breast cancer, with olaparib and talazoparib having demonstrated superior efficacy compared with standard chemotherapy in advanced germline BRCA-mutated cancer. This review describes the biological rationale for PARPi and presents the accumulating data on PARPi use in breast cancer.

Checkpoint Inhibitors in the Treatment of Breast Cancer.

PURPOSE OF REVIEW: The treatment landscape for many cancers has dramatically changed with the development of checkpoint inhibitors. This article will review the literature concerning the use of checkpoint inhibitors in breast cancer. RECENT FINDINGS: The histological subtype of BC with the strongest signal of efficacy has been triple-negative breast cancer (TNBC). Early trials of single-agent checkpoint inhibitors did not demonstrate a uniformly positive signal. Clinical studies suggest response rates between 5 and 10% in pretreated patients and roughly 20-25% for untreated advanced TNBC. However, in the small subset of patients who do respond, the response is often durable. More encouraging results have been reported with their use in combination with chemotherapy in the neoadjuvant setting. Larger phase III studies are underway to confirm these earlier findings. An immune-directed therapeutic approach for the management of BC is underway, and it is likely that combination therapy will be required to achieve a level of efficacy worthy of use in the BC treatment paradigm. These agents are not without both economic and clinical toxicity; therefore, it is imperative that we identify patients most likely to benefit from these therapies through well-designed biologically plausible clinical studies and by evaluating novel combinatorial approaches with informative biomarker driven correlative studies.

Systemic therapy for esophagogastric cancer: targeted therapies.

The poor prognosis for patients with esophagogastric cancers (EGC) has resulted in an increased focus on the use of targeted agents in this disease. Targets include epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), Her2, mammalian target of rapamycin (mTOR), MET, poly (ADP-ribose) polymerase (PARP) and claudin 18.2 (CLDN18.2). Trastuzumab, an anti-Her2 antibody, was approved by the U.S. FDA in 2010 as first-line therapy in combination with chemotherapy for Her2-positive disease. Since then, strategies targeting Her2 that have been successful in Her2-positive breast cancer, have failed in EGC. The one remaining study, the phase III Jacob study with pertuzumab, has yet to be presented. The anti-VEGF receptor 2 antibody, ramucirumab has been investigated as second-line therapy in 2 phase III trials, which resulted in improved survival, with subsequent FDA approval of ramucirumab in the second-line setting. Therapies targeting EGFR have been evaluated in a number of phase III studies, all of which have been negative. Phase III investigation of an mTOR inhibitor did not improve survival, although biomarker studies are awaited which may identify subgroups of patients that may benefit from its use. The results of the trials targeting MET in EGC have been disappointing, raising doubts about the usefulness of further testing agents that inhibit the MET pathway. PARP inhibition with olaparib, warrants further investigation, possibly in combination with other targeted therapies or immune checkpoint inhibition and in a biomarker-selected population. The identification of CLDN18.2 and its targeting with claudiximab is very promising and will be further investigated in a phase III study.

Systemic therapy for esophagogastric cancer: immune checkpoint inhibition.

The poor prognosis for patients with esophagogastric cancers (EGC) requires the development of newer more effective therapies to further improve the treatment outcomes for this disease. Immunotherapy is a novel treatment strategy that is dramatically changing the treatment landscape for several types of cancers. Cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed death the programmed death (PD)-1/PD-ligand are essential immune checkpoint inhibitors that suppress T cell activation. Targeting of these immune checkpoints with monoclonal antibodies has shown clinical efficacy in several solid tumors which has led to their approval and use in routine clinical practice. In EGC early phase evaluation of immune checkpoint inhibitors has yielded encouraging results with multiple phase 3 studies currently ongoing. In this review, the biological rationale for the use of immune checkpoint inhibitors in cancer will briefly be described and the accumulating data concerning their use in EGC will be presented.

Late-onset paraplegia after complete response to two cycles of ipilimumab for metastatic melanoma.

BACKGROUND: Ipilimumab has been shown to improve overall survival in patients with metastatic melanoma; however, complete responses (CRs) are uncommon. Immune-related side effects usually involve the skin or gastrointestinal tract. Neurologic events occur less frequently but are well described. CASE REPORT: We report the case of a 58-year-old man with metastatic melanoma who commenced ipilimumab post spinal decompression and radiation. He developed a colitis post cycle 2 and ipilimumab was discontinued. Imaging, however, documented a radiological CR. 8 weeks later, he developed paraplegia and a myelitis despite an ongoing radiological CR. Steroid use resulted in some improvement radiologically, without clinical improvement. CONCLUSION: We report myelitis with consequent paraplegia as a potential neurological immune-related side effect of ipilimumab. We further describe a patient with a CR after 2 cycles of ipilimumab in the setting of radiation.

Efficacy and safety of vismodegib : a new therapeutic agent in the treatment of basal cell carcinoma.

INTRODUCTION: Basal cell carcinoma (BCC) is the most common human malignancy. Treatment options for the minority of patients presenting with locally advanced inoperable or metastatic BCC are very limited. The hedgehog (Hh) pathway plays a crucial role in the pathogenesis of BCC. Recent advances in targeting this pathway have led to the development of a first-in-class, small-molecule oral Hh inhibitor, vismodegib (Erivedge®, Genentech). AREAS COVERED: In this article, we review vismodegib with regard to its mechanism of action, clinical efficacy, safety and tolerability, and we consider the causes of emerging resistance to the drug. EXPERT OPINION: Vismodegib is a welcome addition to the treatment paradigm for BCC. Approval was based on Phase II evidence, the patient number was relatively small, there was no control group or a comparator group and survival data have not been presented so longer term follow-up and larger exposure to the drug is required to fully appreciate its clinical utility into the future. With ongoing use of the drug in the nontrial population and further studies investigating its use in both early- and later-stage disease, we will get a better understanding of the drug and determine its place in the armamentarium against BCC.