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August 1, 2014

New approaches to the old enemy of breast cancer

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'A 50 per cent decrease in the recurrence of breast cancer was reported in the most recent update of the N9831 trial presented by Edith Perez in San Antonio in 2009'

A number of new drugs and mechanisms show promise, especially in combination, according to breast cancer expert Dr Shanu Modi. Gary Culliton reports.

There are “a number of exciting drugs and novel mechanisms of action” in development in relation to HER2-positive breast cancer, according to Dr Shanu Modi, consultant medical oncologist at the Memorial Sloan-Kettering Cancer Center in New York.

Because they have different mechanisms of action, there is now real potential to “fully attack” the HER2 receptor and pathway in different fashions, she told a recent breast cancer meeting at the Mater Private Hospital. Combination therapy is the way forward, she added.

The current standard of care for HER2-positive breast cancer is trastuzumab — a humanised monoclonal antibody that targets the extracellular domain of HER2. HER2 is still a relevant breast cancer target, after progression on trastuzumab, said Dr Modi.

In a single institution experience report from the MD Anderson Cancer Center in Houston, five-year survival for HER2-positive metastatic breast cancer patients was 19.7 per cent, compared to 24.5 per cent for patients who were HER2 negative (Dawood S et al, 2010). However, when HER2-positive patients were treated with trastuzumab, the five-year survival rates (23.4 per cent) approached those of the HER2-negative patients.

A number of pivotal trials have shown that adding trastuzumab to chemotherapy prolongs survival in metastatic breast cancer (Slamon D et al, 2001; Marty M et al, 2005).

‘Gold standard’
A 50 per cent decrease in the recurrence of breast cancer was reported in the most recent update of the N9831 trial presented by Edith Perez in San Antonio in 2009 (Perez E et al, SABC 2009, N9831 concurrent vs the control arm). There was a statistically significant 35 per cent increase in overall survival (OS) and a 52 per cent increase in disease-free survival (DFS). “Clearly, trastuzumab is the gold standard and the benchmark to which all other HER2-targeted therapies are compared,” said Dr Modi.

The second approved drug is lapatinib, a tyrosine kinase inhibitor. It is now a second line of therapy after progression on trastuzumab. It is predominantly a signal transduction inhibitor. It has been shown that adding lapatinib to chemotherapy, after progression on trastuzumab, leads to statistically significant improvements in time to progression (TTP) and response rates (RR), (Geyer C et al, 2007). Lapatinib is being taken into the adjuvant setting (ALTTO trial for adjuvant therapy).

Paradigm shift
Von Minckwitz (J Clin Oncol. 2009) looked at the role of continuing trastuzumab beyond progression. This represented a paradigm shift in the way chemotherapy drugs are used. Patients with HER2 metastatic breast cancer, who had progressed on chemotherapy plus trastuzumab, were randomised to either capecitabine therapy alone or capecitabine plus a continuation of trastuzumab.

Not only was there an improvement in response rates, clinical benefits and time to progression, there was even a trend towards improved overall survival, through continuing trastuzumab beyond progression.

An approach targeting the HER2 receptor is an “active option”. A study by Scaltriti et al (Oncogene, 2009) looked at preclinical synergy of lapatinib plus trastuzumab in HER2-positive tumour xenografts. This demonstrated greater anti-tumour activity with trastuzumab plus lapatinib, compared to either trastuzumab or lapatinib alone. A trial by Joyce O’Shaughnessy and Kim Blackwell provided clinical support for this. A randomised study of lapatinib alone or in combination with trastuzumab in heavily pretreated HER2-positive metastatic breast cancer patients progressing on trastuzumab therapy looked at the concept of a dual HER2 blockade.

There was an improvement in response rates and a clinically significant doubling of the clinical benefit rate for the doublet. There was a statistically significant improvement in progression-free survival using both targeted therapies, compared to using one alone. Even at six months, there was a persistent doubling of the benefit for the combination versus the single-agent therapy.

Trastuzumab was compared to lapatinib in the NEO-ALTTO trial (Baselga J et al, 2010). Subjects received the same chemotherapy (paclitaxel).

When pathological complete response (path CR) rates were examined, it appeared that as a HER2-targeted drug, trastuzumab might have advantages over lapatinib, said Dr Modi. The third arm of the NEO-ALTTO study looked at lapatinib plus trastuzumab (again in conjunction with paclitaxel). Path CR rates in the breast and lymph nodes were compared. The rates were 20 per cent for lapatinib and 28 per cent for trastuzumab.

When both lapatinib and trastuzumab were used together, however, there was a profound 47 per cent path CR rate. “That is phenomenal,” said Dr Modi. “That approach — hitting more than one point on the HER2 receptor or pathway — is the way forward for this sub-type of breast cancer.”

Promising drugs
Trastuzumab emtansine (T–DM1) is an antibody conjugate. It is linked to a very potent chemotherapy called DM1. It provides intracellular delivery of mertansine (a derivative of maytansine, a natural-product microtubule polymerisation inhibitor, which is 20 to 100 times more potent than vincristine). A 33 per cent response rate was reported in a heavily pre-treated group of patients with this well tolerated single-agent therapy (Krop et al, 2010).

A Phase II trial of T-DM1 examined patients who were HER2 positive and had been previously treated with anthracycline, taxane, trastuzumab, capecitabine and lapatinib. In all, 110 patients were enrolled and the response rate was a “phenomenal” 38 per cent. There was a durable (seven months) response (Krop, ESMO, 2010). The first randomised Phase II data found a response rate of 48 per cent for T-DM1 compared to 41 per cent for another standard of care for HER2 breast cancer, docetaxel plus trastuzumab (Edith Perez, ESMO, 2010). This trial also indicated that it is relatively well tolerated.

'A number of pivotal trials have shown that adding trastuzumab to chemotherapy prolongs survival in metastatic breast cancer'

The large Phase III EMILIA trial, which is currently comparing T-DM1 with capecitabine plus lapatinib, also has a primary end point of progression-free survival.

Another monoclonal antibody therapy is pertuzumab, which binds to a different epitope to trastuzumab on the HER2 extracellular domain. It functions as an antibody, but it has been dubbed a dimerisation inhibitor (Hubbard, 2005).

There appears to be great synergy for pertuzumab and trastuzumab in HER2-positive animal models (Scheuer W, Cancer Research 2009). There is greater anti-tumour activity with the two drugs combined than with either on its own.

Both antibodies were given intravenously every three weeks in Jose Baselga’s Phase II trial of pertuzumab plus trastuzumab in HER2-positive patients progressing on trastuzumab (JCO 2010). The overall response rate was 24 per cent. The clinical benefit rate was 50 per cent. Progression-free survival was described as “robust”.

At the San Antonio Breast Cancer Symposium last year, Prof Luca Gianni from the Istituto Tumori di Milano presented Phase II study results of the NeoSphere neoadjuvant HER2 trial. The addition of pertuzumab to trastuzumab and the chemotherapy drug docetaxel had an impressive rate of tumour eradication (46 per cent), which is half again as much as was achieved with docetaxel and trastuzumab, the standard therapy. Jose Baselga’s CLEOPATRA randomised Phase II trial is due to present results soon.

New research
Dr Modi has done research in the area of heat shock protein 90 (Hsp90), a widely expressed molecular chaperone protein. A number of the client proteins to which Hsp90 is linked are key oncogenic signalling proteins. If Hsp90 is inhibited, the client proteins it supports become unstable and they are ultimately degraded. Tanespimycin (17-AAG) is a natural product that binds to Hsp90 and inhibits its activity, thereby inducing the degradation of these clients. When cells are treated with tanespimycin, there is a complete loss of the HER2 protein 24 hours later, she said.

Many of the known mechanisms of resistance to trastuzumab — such as p95, IGF-1, EGFR and AKT activity — are susceptible to Hsp90 inhibition.

There is a rationale for combining the two agents, trastuzumab and tanespimycin, she added.

Dr Modi published results of a Phase I trial of tanespimycin plus trastuzumab in the Journal of Clinical Oncology in 2007. The study concluded that tanespimycin plus trastuzumab therapy is well tolerated and has anti-tumour activity in patients with HER2-positive breast cancer whose tumours have progressed during treatment with trastuzumab.

The data suggested that Hsp90 function could be inhibited in vivo to a degree sufficient to cause inhibition of tumour growth.

Dr Modi’s team then focused on HER2-positive metastatic breast cancer. A Phase II trial, conducted jointly with the Arizona Cancer Center (Clinical Cancer Research 2011), looked at patients who had progressed on trastuzumab therapy. The vast majority of patients on the trial had benefit.

A biotech company called Infinity has a prodrug, IPI-504, which can convert to tanespimycin within the cell. The same clinical data apply. Dr Modi has recently completed a Phase II trial, using IPI-504 plus trastuzumab in patients with HER2-positive breast cancer.

A ‘next generation’ of Hsp90 inhibitors are in development. There has been a move away from geldanamycin drugs (such as tanespimycin), to synthetic small molecule inhibitors. These may have an advantage. They are oral and have less phytotoxicity.

PU-H71 is an inhibitor made by Gabriella Chiosis, one of the scientists at Memorial Sloan-Kettering Cancer Center. Pre-clinically, this drug has some of the most profound anti-tumour effects, particularly in triple negative breast cancer. A Phase I trial is expected to start shortly.
Therapy response ‘may be predicted’
Dr Kathleen Pritchard, consultant medical oncologist at the Sunnybrook Health Sciences Centre in Toronto, considered whether the 21-gene assay Oncotype DX might be used to predict the patients most likely to respond to an endocrine therapy and whether chemotherapy should be added. It is possible to predict for HER2-directed therapy, the meeting at the Mater Private Hospital heard.

HER2 over-expressing patients are more likely to respond differentially better to anthracycline-containing regimens, than are patients who are not over-expressing HER2. The same phenomenon was observed in the Topo II study. Recently, John Bartlett and others have shown that chromosome 17 (Ch17) polysomy is a predictor of anthracycline response. A meta-analysis (Pritchard, 2008) looked at HER2 and Topo II, a marker that predicts anthracycline’s activity in early breast cancer patients.

Oncotype Dx is a breast cancer test that predicts the likelihood of recurrence in an individual woman within 10 years and the likely benefit from chemotherapy. With a low Oncotype DX response score, patients have much lower recurrence rate and with a higher score, they have a higher rate.

With the high-risk score, the effect of endocrine therapy does not appear to be as high. It may be in that group that chemotherapy is a better option. There is also a role for genetic referral and genetic counselling, according to Dr Mark Robson, Consultant Medical Oncologist, Memorial Sloan Kettering Cancer Center in New York.