This is an annual multi-disciplinary meeting that brings together surgeons, scientists, radiologists and oncologists to debate and discuss the current issues in breast cancer. It is attended by a lot of community oncologists from small (1-4 person) practices who do not have the time or inclination to go to ASCO or the SABC Symposium. This is a neat way for them to get the distilled version of what’s actually happening in a single tumour, making the lessons learned easier to digest.
Miami Breast Cancer Conference link
Of course, the big news from a clinical perspective was focused on trastuzumab (Herceptin) and the aromatase inhibitors in the adjuvant setting as well as bevacizumab (Avastin), in combination with AC or carboplatin and dose dense paclitaxel in the metastatic setting. The Herceptin adjuvant data was stunning; there were 4 trials all reported in the same session when it was first presented at ASCO last year. Perhaps the most dramatic of the 4 studies was the joint analysis of the N9831 and NSABP B31 trials; 5,000 people gasped at the same time when the survival slide was put up! After 4 years, the survival in the Herceptin arm was 85% compared to only 67% in the control arm, which was very highly significant (P<0.00001, or thereabouts). Perhaps someone needs to put a package together for the UK, so that HER-2 positive women there can ALL receive the benefit of the treatment and not have to worry about the vagaries of a postal code lottery.
What was interesting is that a number of the experts have clearly changed their perspective on treatment over the course of the last 12 months, which will ultimately have a wider effect as the impact of the above mentioned drugs trickles down to the community level. The good news is that women will be living longer, with not too much compromise on the toxicity side. The bad news is that if you have a related drug (e.g. a taxane such as docetaxel) then data in combination with trastuzumab or bevacizumab will clearly be needed to convince the oncologists to use alternatives, otherwise dose-dense paclitaxel will exert a stranglehold as the base chemotherapy with the new biologic combinations.
Actually, the most riveting talks of the day were two on science; Dr Lance Liotta on apoptosis and Dr Kent Osborne on blocking cross talk between ER and GFR to circumvent endocrine resistance. Apoptosis is programmed cell death, which all normal cells have. The cancer cell is very different – it lacks the death switch and continues to live and proliferate.
Liotta believes that the drug targets of the future are proteins driving deranged or hyperactive cancer signal pathways. He posed an interesting question for the audience. Does chemotherapy amplify apoptosis or suppress growth? He went to explain that cancer is a disease of the cellular signal network and genetic mutations either cause the network to be perpetually active or mutations and deletions deactivate suppressor proteins. The cancer cell thus becomes addicted to hyperactive stimulation.
Thus, in the long run, tracking down these aberrant mutations and switching them off will lead to higher efficacy, lower toxicity and reduced recurrence. This neat theory got me thinking – essentially what Liotta described is how targeted therapies such as Herceptin and Gleevec work by switching off the kinase activation associated with HER-2 and Bcr-Abl respectively.
Ultimately, it should be possible to complete a circuit mapping of the tissue microenvironment leading to apoptosis regulation or suppression and activation of the Akt/Bad prosurvival pathway. The end result would be like allowing the cancer cells to kill themselves, like a normal cell does naturally, by giving them a gun.
There was an interesting example of this theory at work using children with rhabdomyosarcomas, a rare but often fatal disease. Liotta looked at it in two different ways; why do some patients fail therapy (or the therapy fail the patient) and what is different about their cancer that allows this happen? Basically the answer was that the non-survivors had suppression of apoptosis. They tested this concept in a small study using an mTor inhibitor CCI-779 (temsirolimus) using pulse treatment prior to giving the standard chemotherapy. This strategy was a success and some non-responders were converted into responders; by amplifying apoptosis, they enabled the chemotherapy to work.
mTor is a downstream substrate of the Akt pathway which has been shown to affect apoptosis. Temsirolimus is currently undergoing clinical trials in a number of different indications. The idea of using it prior to chemotherapy rather than in combination is a very elegant and attractive one based on the two examples given. It also demonstrates how signal pathway proteins could be the targets of the new class of signal transduction inhibitors.
Kent Osborne’s talk on blocking cross-talk between the estrogen receptor and growth factor receptor to circumvent endocrine resistance was equally compelling. He used a series of simple but effective cartoons to explain how resistance to ER occurs and what techniques might be helpful in overcoming it. Unfortunately, his talk was so riveting that I forget to draw the cartoons! The basic upshot was that the AI’s might be more effective than tamoxifen, at least initially, in preventing tumour growth because they decrease estrogen levels and do not activate the extracellular ER receptor. He postulated that increasing GFR activity (which stimulates the extracellular ER) causes de novo tamoxifen resistance.
On a similar note was an excellent cartoon explaining how GFR activity in HER-1, HER-2 and HER-3 can be linked to EGFR resistance unless all three are effectively blocked, because trastuzumab, gefitinib and erlotinib all inhibit only one of the GFRs. Pertuzumab and lapatinib were mentioned as pan-ERB inhibitors but neither is particularly potent and doesn’t do the job well enough, so new pan-ERB agents will still be needed. From a marketing perspective, this is a very clear case of comparing the first in class vs. the BEST in class strategy.
Osborne’s concept is a very simple but potentially game changing one for targeted therapies:
1. Determine the pathways driving the tumour
2. Identify specific targets
3. Consider all or redundant pathways (these lead to resistance)
4. Block ALL possible pathways (otherwise there will be limited success)
This idea can be applied to virtually every cancer – in many cases, the first 2 are clearly met, but maybe more focus and research needs to be applied to 3) because if you give the cancer cell an out, it is wily enough to figure it out in the end. Obviously, for 4) combination therapies may need to be tested in order to allow the original standard to continue working effectively. This strategic approach would likely work just as well for leukemias such as AML and CML as it would for solid tumours.
Taking this step forward, I realized that Gleevec achieves the first 2 steps very nicely in CML, but it doesn’t block Src. Src mutations, when they occur, are associated with increased resistance, so it would be logical to block both Bcr-Abl and Src to avoid resistance developing. Whether this means that dasatinib, which inhibits Bcr-Abl and Src, should replace Gleevec or used in combination is an avenue that needs to be explored. There may be other downstream pathways of Bcr-Abl that could also be involved in resistance over time.