Highlights of the Chemotherapy Foundation Symposium XXVII: therapeutic options for breast cancer

Abstract

The XXVII Annual Chemotherapy Foundation Symposium sponsored by The Mount Sinai School of Medicine is one of the leading forums for communication of important discoveries and new developments in cancer therapeutics. Here, we summarize and review the emerging advances in the treatment of breast cancer, which includes therapeutics in HER signaling, poly(ADP-ribose) polymerase inhibition, PI3K inhibitors and novel epithilones.

Keywords::

• breast cancer
• PARP inhibition
• PI3K inhibitors
• T-DM1

Breast cancer is the most common non-cutaneous cancer in women in the Western world; the lifetime risk of developing invasive breast cancer in the USA is 12.6% (one out of eight women) [1]. The HER2 oncogene, or its protein receptor, HER 2, is amplified or overexpressed in approximately 25–30% of breast tumors [2]. HER2 overexpression has been reported to be a poor prognostic factor and a predictive risk factor for decreased disease-free and overall survival in patients with breast cancer [3].

Approximately a third of HER2-overexpressing metastatic breast cancers respond to single-agent trastuzumab, with almost two-thirds responding to combination taxane–trastuzumab regimens [2,4]. However, responses are short-lived, averaging less than 1 year. In the adjuvant setting, approximately 15% of patients still develop metastatic disease despite trastuzumab-based therapy [5].

One portion of the symposium was dedicated to HER signaling and therapeutics. A significant level of compensatory cross-talk occurs among receptors within the HER family [6]. Although, trastuzumab reduces HER2-mediated signaling, it does not reduce signaling from other HER receptors. The heterodimer formation of HER2/HER3 has been demonstrated to directly activate the PI3K pathway and prevent trastuzumab-mediated growth inhibition. A HER3 total protein (H3T) assay has been developed and data, which predict trastuzumab response, were reported by Allan Lipton from the MS Hershey Medical Center (PA, USA) [7]. In HER2-overexpressing patients, high H3T expression predicted shorter median time to progression (n = 25; median TTP: 6.1 months) compared with low H3T expression (n = 30; median TTP: 13.1 months; HR: 2.7; p = 0.0002). This assay could potentially implicate a patient population requiring additional HER2-directed therapeutic interventions.

Regarding HER2-targeted therapy, the immunoconjugate trastuzumab–DM1 (T-DM1) was designed to combine the biological activity of trastuzumab with the targeted delivery of a highly potent antimicrotubule agent, DM1, a maytansine derivative, to HER2-expressing breast cancer cells. The aim of immunoconjugates such as T-DM1 is to target intracellular delivery of both drugs with high specificity to avoid normal tissues.

Phase II data with T-DM1, dosed at 3.6 mg/kg intravenously every 3 weeks and assessed every two cycles for toxicity and efficacy, was reported by Harold Burstein from the Dana-Farber Cancer Institute (MA, USA) [8]. The primary end point was the overall response rate; the objective overall response rate was 39.3% (95% CI: 30–49), and the confirmed overall response rate, repeat imaging done on two occasions more than 4 weeks apart, was 27% (95% CI: 19.4–36.1). Of the 62 patients exposed to prior lapatinib therapy, 60 were evaluable for efficacy. Objective responses were observed in 23 out of 60 (38.3%; 95% CI: 19.4–36.1). The most common adverse events were fatigue, nausea and headache. Grade 3 and 4 adverse events included thrombocytopenia (eight out of 112), hypokalemia (six out of 112), and fatigue (four out of 112), This finding establishes that HER2 remains a viable target in HER2-overexpressing breast cancer, even after trastuzumab has become ineffective.

Secondary to the safety and efficacy of T-DM1, two additional studies are underway; a Phase III, randomized trial designed to compare T-DM1 with capecitabine and lapatinib in patients with HER2-positive metastatic breast cancer and a Phase II trial comparing T-DM1, administered as a single agent, to trastuzumab plus docetaxel as a first-line treatment in metastatic HER2-positive breast cancer.

A second portion of the symposium focused on poly(ADP-ribose) polymerase (PARP) inhibition. Cynthia Osborne from the Baylor Charles A. Sammons Cancer Center (TX, USA) reported on PARP inhibition, and it appears to be a promising therapeutic strategy. A Phase II trial of AZD2281 (olaparib; 400 mg twice daily) in 24 patients with BRCA1–2-associated breast cancer revealed objective response in nine patients (38%); a significant proportion of sporadic triple-negative breast cancers share the molecular make-up of BRCA1–2 associated breast cancers [9].

A randomized Phase II trial in 116 patients with triple-negative breast cancer compared carboplatin (AUC: 2; day 1, 8) and gemcitabine (1000 mg/m² day 1, 8; every 3 weeks) alone or in combination with the PARP inhibitor BSI-201 (5.6 mg/kg intravenously at day 1, 4, 8, 11) revealed significantly improved response rates (48 vs 16%; p = 0.002), clinical benefit rate (62 vs 21%; p = 0.0002), median progression-free survival (6.9 vs 3.3 months; HR: 0.342; p < 0.0001), and overall survival (9.2 vs 5.7 months; HR: 0.348; p = 0.0005) for the PARP inhibitor arm [10]. Hematologic and nonhematologic toxicities (nausea, vomiting, fatigue, neuropathy and diarrhea) did not differ between the two treatment groups, nor were there any substantial differences between the two treatment groups with regard to gemcitabine/carboplatin dose reductions.

A third portion of the Symposium focused on novel therapeutics. Howard Burris from the Sarah Cannon Research Institute (TN, USA) discussed PI3K inhibitors, such as SF1126 and XL147, which are currently in Phase I pharmacokinetic and pharmacodynamic evaluation. Both agents appear to be well tolerated. XL147 has been demonstrated to potentiate the antitumor efficacy of cytotoxic agents such as paclitaxel and carboplatin; partial response occurred in four patients (26%) who had been previously been treated with a platinum-containing regimen. In addition, a platinum-naive patient with triple-negative, inflammatory breast cancer experienced regression of cutaneous lesions after two cycles.

On a final note Andrew Seidman from Memorial Sloan-Kettering Cancer Center (NY, USA) discussed patupilone, an epithilone which crosses the BBB in animal models, and has shown minimal activity in patients with breast cancer brain metastases progressing or recurring after whole brain radiation therapy [11]. This Phase II study reported partial response in six patients (19%), stable disease in nine patients (29%), and progression of disease in 16 patients (52%). The most common treatment-related grade 3 or greater event was diarrhea (grade 3 in 30% of patients). Accrual to this protocol continues.

The 27th annual Chemotherapy Foundation Symposium was successful in communicating the emerging advances in the treatment of breast cancer. These developments provide us with optimism for the future, but further investigation of these agents will need to focus on of the mechanisms of resistance and toxicity, so that they can be integrated into treatment schemes safely.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.