PRACTICAL APPLICATIONS

In unselected breast cancer, platinum salts have only modest activity, with overall response rates between 32%-54% and low patient tolerability.¹,² As a result, platinum salts are not commonly used in the treatment of breast cancer. However, platinum salts may have a place in the treatment of patients with TNBC. Up to 20% of patients in the United States diagnosed with breast cancer are triple negative (progesterone-receptor, estrogen-receptor, and HER2 negative). Patients with TNBC have limited treatment options, but TNBC is phenotypically and molecularly similar to BRCA1-asssociated breast cancer, which has been shown in in vitro studies to have increased sensitivity to bifunctional alkylating agents, such as mitomycin C and platinum drugs.¹

The potential effectiveness of platinum salts in TNBC was demonstrated in a retrospective analysis of patients from the Royal Marsden hospital in the United Kingdom. In this review, 62 patients who had been treated with neoadjuvant platinum-based regimens were confirmed to have TNBC. The complete response rates were significantly higher for patients with TNBC (88%) compared to other patients (51%; P=0.005); survival was worse in patients with early TNBC, but was improved in those with advanced TNBC.¹

The responsiveness of TNBC to neoadjuvant single-agent cisplatin was shown in a small trial in 28 women with stage II or III TNBC. These patients were treated with four cycles of neoadjuvant cisplatin and then underwent surgery followed by treatment with standard adjuvant chemotherapy with or without radiation. In this trial, 22% of patients achieved a pathologic complete response and 64% achieved a complete or partial clinical response. This study also identified biomarkers that showed potential in predicting cisplatin response.³

While these results are promising, more trials are needed to determine the best treatment strategies in TNBC with platinum salts and to confirm their efficacy.

Anti-HER2 therapies have been proven to be an important option in treating patients with breast cancer that overexpresses HER2. However, patients still progress when treated with these therapies, which has fueled the development of new strategies and agents. Among these strategies is the combination of anti-HER2 agents with different mechanisms of actions. For example, trastuzumab, a monoclonal antibody, and lapatinib, a small molecule tyrosine kinase inhibitor, are anti-HER2 therapies that interfere with the HER2 pathway in different ways.

In the GeparQuinto trial, both trastuzumab and lapatinib were shown to produce responses in patients with HER2-overexpressing breast cancer, although responses with trastuzumab were higher. In this study, 620 patients were randomized to receive epirubicin/cyclophosphamide for four cycles, followed by docetaxel for four cycles, with concomitant treatment with trastuzumab or lapatinib. After undergoing surgery, patients received either trastuzumab for 6 additional months or lapatinib for 12 months. Patients in the trastuzumab arm achieved a significantly higher pathologic complete response rate (pCR; 50.4%) compared to those in the lapatinib arm (35.2%; P<0.05).⁴

The NeoALLTO trial evaluated whether trastuzumab and lapatinib used in combination would be more effective than either agent used alone. In this trial, 455 patients were randomized to trastuzumab alone, lapatinib alone, or combination trastuzumab and lapatinib for up to 52 weeks of anti-HER2 therapy. Patients received the treatments as neoadjuvant therapies and then again after they underwent surgery and completed standard adjuvant chemotherapy (FEC).⁵ The pCR was higher in patients in the combination arm (51.3%) compared to the trastuzumab-only arm (29.5%) and the lapatinib-only arm (24.7%).⁶

Similar results were seen in the CHER-LOB trial. In this study, patients received neoadjuvant chemotherapy (paclitaxel plus FEC) with either trastuzumab alone, lapatinib alone, or a combination of both. As in the NeoALLTO trial, the pCR in the combination arm was higher (43.1%) than for either trastuzumab (25.7%) or lapatinib (27.8%) alone.⁷

A triplet of therapies showed promise in treating HER2-positive disease in the Neosphere trial. In this trial, neoadjuvant therapy with trastuzumab, pertuzumab, and docetaxel was evaluated in 3 arms that included combinations of 2 agents and 1 arm with all 3 agents. After surgery, patients received standard chemotherapy (FEC) followed by trastuzumab.^6,8 The pCR was significantly increased in the triple-therapy arm (45.8%) compared to the double-therapy arms of trastuzumab plus docetaxel (29.0%; P=0.0141), pertuzumab plus docetaxel (24.0%; P=0.003), and trastuzumab plus pertuzumab (16.8%).⁶

Although these trials yielded positive results, an increase in pCR has not yet been associated with statistically significant improvements in survival. As a result, more studies are needed to confirm that the use of doublets or triplets to treat patients with HER2-overexpressing breast cancer are necessary. Other studies are ongoing to evaluate different combinations of therapies.

In an early phase III clinical trial, overall cardiotoxicity was 27% when trastuzumab was added to anthracycline-based chemotherapy and 13% when added to paclitaxel. For future trials, strict guidelines were developed that included avoiding concurrent use of anthracyclines with trastuzumab, following strict cardiac exclusion criteria, and using rigorous prospective cardiac monitoring. With the implementation of these guidelines, the difference in the rate of cardiac death and severe congestive heart failure (HF) seen with trastuzumab compared with other regimens was less than 4%.⁹ Despite these advances, in clinical populations, symptomatic heart failure occurs in 1% to 4% of patients treated with trastuzumab and left ventricular ejection fraction decreases in 10% of patients.¹⁰

Prior anthracycline use and advanced age have been clearly identified as independent risk factors for cardiotoxicity. The most commonly used anthracycline derivative, doxorubicin, has been shown to increase the risk of HF >5% when the cumulative dose exceeds 450 mg/m². A recent study showed that women between 66 and 70 years of age who were treated with anthracycline-based chemotherapy had a significantly higher risk of HF (47%) than those treated with nonanthracycline-based chemotherapy (33%).¹¹

Data about other risk factors for cardiotoxicity in trastuzumab are not clear, but they are expected to be similar to those related to anthracyclines. Analysis of results from clinical trials for trastuzumab — NSABP-B31 and HERA — identified a number of factors associated with an increase in cardiotoxicity, including older age, lower baseline LVEF and lower post-AC LVEF, treated hypertension, and a body mass index >25. Radiotherapy to the chest wall was not associated with an increased risk.¹¹

Despite the fact that African American women have a lower lifetime incidence of breast cancer than Caucasian American women, they have a higher mortality rate. African American women are also more likely to be diagnosed at a younger age and with higher grade tumors that are triple negative. According to a number of studies, the frequency of TNBC in African American women ranges from 20.8% to 46.6%.¹²

The higher rate of mortality is undoubtedly related to many different factors; however, socioeconomic conditions certainly play an important role. African American women are more likely to be initially diagnosed at a more advanced stage, which is due to delays in diagnosis and treatment that are associated with the higher poverty rates and barriers to access to healthcare that are more common in the African American patient population. However, the increased frequency of TNBC in African American women may also be due to genetics. It has also been postulated that African American ancestry may play a role. If so, studies in African American and African women may help identify tumor or germline markers that might be helpful in developing targeted therapies for high-risk disease.¹²

In the past, when patients progressed on trastuzumab, the agent was discontinued and patients were treated with other therapies, such as lapatinib or capecitabine. More recently, National Comprehensive Cancer Network (NCCN) guidelines have recommended continuing trastuzumab-containing regimens. Preclinical data have demonstrated that trastuzumab inhibits tumor cell proliferation and enhances the effectiveness of taxanes in tumors that progress on trastuzumab alone. By contrast, when trastuzumab is stopped, tumor cell regrowth is rapid.¹³

A number of trastuzumab-containing combination regimens have been shown in clinical trials to be effective in treating patients with HER2-positive disease that has progressed after treatment with adjuvant trastuzumab. A phase III trial showed that the combination of lapatinib with trastuzumab was superior to lapatinib alone for progression-free survival (PFS; 12.0 weeks vs. 8.1 weeks; HR=0.73; P=0.008). In this trial, there was no difference in overall response rate, but there was a trend for improved overall survival (OS) in the combination arm. In a phase II single-arm trial of 66 patients, the combination of pertuzumab and trastuzumab resulted in an objective response rate of 24.2% and a median PFS of 5.5 months.¹⁴ In a phase I/II trial of 47 patients, the combination of trastuzumab with everolimus, an inhibitor of mammalian target of rapamycin (mTOR), showed partial responses in 15% of patients, persistent stable disease (>6 months) in 19%, and a median PFS of 4.1 months.¹⁵

Lapatinib, another anti-HER2 agent, is active as a single agent but has been shown in several trials to be more effective in combination with other agents. In a phase III trial in 399 women, the addition of lapatinib to capecitabine in women with advanced breast cancer that had progressed on trastuzumab prolonged time to progression (HR=0.57; P<0.001) and showed a trend toward improved OS (HR=0.78; P=0.045).¹⁶

Taxanes are microtubule-targeting agents that are highly active against breast cancer and have become standard therapies for treating early and advanced disease. Microtubules play an important role in many different cellular functions, including cell division, growth, and motility. In recent years, non-taxane microtubule-targeting agents have been investigated in breast cancer.¹⁷

A synthetic analogue of halichondrin B, a macrolide found in the sea sponge, is a novel microtubule modulator.¹⁸ Eribulin mesylate has been approved for “the treatment of patients with metastatic breast cancer who have previously received an anthracycline and a taxane in either the adjuvant or metastatic setting and at least two chemotherapeutic regimens for the treatment of metastatic disease.”¹⁹ In the phase III EMBRACE study, 762 women with locally recurrent or metastatic breast cancer were randomized to eribulin mesylate or physician’s choice of treatment. Median OS was significantly improved in the eribulin mesylate arm (13.1 months) compared to the treatment of choice arm (10.6 months; P=0.041). The most common adverse events in both arms were neutropenia and asthenia or fatigue.²⁰

Developed from fermenting myxobacterium S. cellulosum, epothilones are another class of non-taxane microtubule-targeting agents. The epothilone ixabepilone has been approved for use as a single agent or in combination with capecitabine for patients with MBC or locally advanced breast cancer that is resistant to anthracyclines or taxanes.²¹ In a phase III trial of 752 patients with MBC resistant to anthracyclines and taxanes, PFS was significantly prolonged in the combination arm of ixabepilone and capecitabine (5.8 months) compared to the capecitabine arm alone (4.2 months; P=0.0003).²²

Although they show activity in this difficult-to-treat patient population, non-taxane microtubule-targeting agents are used further along the treatment continuum — often even later than the third-line for which they have been approved. The optimal role of these agents in treating MBC and advanced disease has not yet been determined.

Lapatinib plus capecitabine has been shown to be effective in patients with HER2-positive advanced breast cancer that has progressed after treatment with regimens that included an anthracycline, a taxane, and trastuzumab. The pivotal trial for this agent included 324 women randomized to lapatinib plus capecitabine or capecitabine alone. The trial was stopped at the time of interim analysis because the results met specified criteria for superiority of the combination therapy. The combination arm achieved a median time to progression of 8.4 months compared to 4.4 months in the capecitabine-only arm.²³

Although lapatinib and capecitabine have shown favorable results, other novel agents are also showing promise in this heavily pretreated population:

The BSI-201 trial evaluated the combination of iniparib with gemcitabine and carboplatin in MBC, but the primary analysis did not show an improvement in PFS or OS. However, an exploratory analysis looking at PFS and OS by prior therapy suggested that there may be potential benefit in patients receiving treatment second- and third-line; confirmatory studies are needed.²⁸

Although disappointing, it should be noted that the understanding of PARP inhibition is still evolving, and the results of BSI-201 should therefore be assessed carefully. These particular results may be due to the fact that iniparib appears to have a mechanism of action different from other PARP inhibitors.²⁹ A recent pharmacodynamics and pathway analysis of iniparib suggested that, unlike other PARP inhibitors, it does not inhibit PARP1 or PARP2.³⁰

One important aspect of integrating PARP inhibition into treatment options for breast cancer is optimizing the mechanism of action. PARP1 is involved in DNA repair, and through its inhibition, the cytotoxic effects of alkylating agents can be enhanced. Much of the clinical development of PARP inhibitors is focused on two approaches: identifying and targeting cells that are most sensitive to PARP activity, such as BRCA-deficient cells; and enhancing PARP inhibition by combining it with DNA-damaging therapy.³¹ Clinical trials are needed to help determine the potential role of PARP inhibition in breast cancer. A number of different trials of PARP inhibitors, such as VELIPARIB, ABT-888, and olaparib, are ongoing.

Chemotherapy sensitivity and resistance assays, or CSRAs, use in vitro analysis of tumor cells collected before or after treatment with chemotherapy to determine if an individual patient or a disease will be sensitive or resistant to a specific treatment. The American Society of Clinical Oncology Technology Assessment Committee recently reviewed and updated the 2004 guidelines on CSRAs. The update committee reviewed 1,298 articles that were published between December 1, 2003, and May 31, 2011. Only 5 randomized controlled trials met predefined criteria and were included in the data review.³²

Despite the growing interest in these products and the potential importance of these analytic strategies, the guidelines note that “review of the literature does not identify any CSRAs for which the evidence base is sufficient to support use in oncology practice.” As a result of this assessment, the guidelines do not recommend the use of CSRAs outside of the setting of a clinical trial. Instead, they recommend that oncologists should choose treatments “based on published reports of clinical trials and a patient’s health status and treatment preferences.”³²

The role of antiangiogenic therapy in breast cancer remains controversial. On November 18, 2011, the FDA revoked the approval of the breast cancer indication for the anti-VEGF monoclonal antibody bevacizumab because “it has not been shown to provide a benefit, in terms of delay in the growth of tumors, that would justify its serious and potentially life-threatening risks. Nor is there evidence that use of bevacizumab will either help women with breast cancer live longer or improve their quality of life.”³³

Previously, bevacizumab had received accelerated FDA approval for breast cancer based on the results from the ECOG 2100 trial, which showed that patients treated with bevacizumab plus paclitaxel had a median PFS of 11.3 months compared to 5.8 months with paclitaxel alone. However, there was no improvement in OS and quality of life scores. In addition, the efficacy and safety analyses were incomplete because of the accelerated approval.³⁴

In the AVADO trial, patients received docetaxel with placebo or a low or high dose of bevacizumab. The bevacizumab arms saw a benefit in tumor response and a small, but significant, increase in PFS. Although there were no differences in OS between arms that included bevacizumab, there was a higher incidence of severe adverse events in those arms. Another trial, the RIBBON-1, randomized patients to taxanes, anthracyclines, or capecitabine with placebo or bevacizumab. Similar to AVADO, this trial showed small increases in tumor response rates and PFS, but no improvement in OS. Once again, patients treated with bevacizumab experienced more serious adverse events.³⁴

Despite this setback, bevacizumab may continue to have a role in the treatment of breast cancer. Other trials investigating bevacizumab in breast cancer are ongoing. It is hypothesized that certain subsets of patients may benefit, such as those with higher VEGF levels or triple-negative disease.