Saturday, May 26, 2012

Pertuzumab: Herceptin Resistance Fix?

About a week ago I came across an article that described a woman who was diagnosed with metastatic breast cancer and was told that unfortunately, she did not have much left to live. She, her family, and friends shared the below video of her sharing her story of her fight against breast cancer and plead to Genentech to allow an early release of the drug Pertuzamab on the basis of compassionate use. Fortunately, the drug was planned to enter the market early June, so Genentech granted her plea.
This sparked my interest in the drug Pertuzamab and lead me to find out why this woman saw the drug as her only hope for survival.

We discussed this week in Dr. Islas' class how cancer patients when treated chemotherapy will often have a relapse in their cancer years later. He specifically  mentioned that this is prevalent in breast cancer patients who have been initially treated with the drug herceptin can often experience a cancer relapse which is herceptin resistant. This, as we studied, is because of the presence of two different cells types associated with a developing tumor, a dominant rapidly expanding type, and a less dominant type that is not as aggressive. The dominant cells are usually inhibiting the proliferative growth of the second set of cells. However, once the dominant cells are treated with chemotherapy, the less dominant type will use this window to regrow, thus causing a relapse in cancer. Because the less dominant cells were unaffected by the chemotherapy that was used for initial treatment, they are resistant to it still after growth.
What I understood from the initial articles that I had read and the woman's posted video was that Pertuzamab was an answer to this problem providing relief for cancer patients that have been treated with herceptin and are experiencing a relapse. In order to understand whether or not my inferences were correct, I read the following article: "Pertuzumab plus Trastuzumab plus Docetaxel for Metastatic Breast Cancer" published by the New England Journal of Medicine January 12, 2012 (2*).

The clinical name for Herceptin is Trastuzumab. As indicated by the name it is a monoclonal antibody that was developed for the treatment of metastatic breast cancer, specifically those with the gain of function mutation in the HER2 receptor. Trastuzumab binds to subdomain IV of the HER2 extracellular domain and exerts its antitumor effects by blocking HER2 cleavage. This inhibits the ligand-independent mitogenic signaling of the HER2 receptor. The signals expressed by the HER2 receptor support and promote cell growth, survival, adhesion, migration, and differentiation (2*). While Trastuzumab has improved the prognosis of patients experiencing metastatic breast cancer, all patients treated with the drug will eventually progress (3*).
Pertuzamab is also a monoclonal antibody that binds to subdomain II of the HER2 receptor. This is a different epitope and thus works complimentary too Trastuzumab. Pertuzamab has the same effect on tumors as HER2 (2*). It is suggested the dimerization occurs between different HER receptors which promote the oncogenic signaling process (HER2:HER3), this fact is used as an explanation as to why all patients with metastatic breast cancer will experience progression eventually. Pertuzumab is believed to inhibit the dimerization of HER2 with other HER molecules, therefore linking it to increased patient prognosis (3*).
Also used in the study was the drug Doxetaxel which is also known as Taxotere, this drug is known to be administered to tumors that have not been receptive to chemotherapy. Doxetaxel is inhibits mitotic development of dividing cells by binding to microtubules arresting them at the G2/M phase (4).

Methods (2*)
The clinical trials for Pertuzamab conducted with patients that, "...had locally recurrent, unresectable,
or metastatic HER2-positive breast cancer." The drug was administered along with a placebo to 800 women total. The study was conducted to ensure randomization, with the goal of presenting Pertuzumab as a drug to be administered with Trastuzumab for any patients with gain of function mutation on HER2. Allowing the drug to be more applicable with more widespread administration.

The above figure describes the characteristics and the range of the patients that were given the drug. As can be seen there was a wide variety of patients that received treatment. Women with metastatic cancer receiving chemotherapy for the first time and women with a relapse of metastatic breast cancer receiving secondary treatment.
I feel however, that women receiving primary chemotherapy and women experiencing cancer relapse should have been separated in the study. This would have lead to a better understanding of the scope and effects of Pertuzumab.

Results (2*)
Women given Pertuzumab vs. control showed an increase in patient prognosis, with a median increase of 6.1 months to patient survival, this is an overall increase in survival of 33% as compared to those given the placebo. Below is a Kaplan-Meier plot indicating the results of the clinical trial.
The patients were tracked and recorded for data up to 45 months, which is about 3.75 years. While this is a prolonged period of time, I felt that the clinical trial should cover at least 5 years and patient relapse should be recorded as well; providing an understanding of secondary localized tumor response to Pertuzumab.
We know, that HER2 breast cancer that has been treated has a high percentage of anti-HER2 resistant relapse. It should be required, in my opinion for these women to be further tested and observed to understand the percentage of them that experience relapse. Placebo vs. Petuzumab to better understand the drugs effects. It may very well be the the percent of relapse is higher or lower in either of the cases and it is important information for the oncologist and patient to have.

Discussion and Conclusions (2*)
The two analyses of the figures which I observed can be explained as follows,
For Figure 1 the issue brought up was that women experiencing breast cancer diagnoses for the first time and those that have experienced relapse were not separated. From the point of views of the directors of the trials this can be understood because the goal of the trial was to experiment the use of Pertuzumab along with Trastuzumab as a complimentary drug to improve patient's general prognosis. This is proven because the women that were experiencing metastatic breast cancer for the second time were only included in the study if Trastuzumab has been concluded as being effective on the relapsed cancer. Looking at the results and conclusions of the experiment, this goal was satisfied, and Pertuzumab was determined to be a success as it improved patient prognosis by 33% overall.
However I feel that these women should have been separated in the trial. These are two different patient situations that should not be grouped into one lump.
For Figure 2 the length of analysis for patient prognosis was my main issue. Again, because the clinical trial had a very general goal, this was not added. Understanding of patient relapse is crucial to patient care, and this is very important information that has not been analyzed. My inference to the question of patient relapse, is that Pertuzumab's effect will not be greater in any way to Trastuzumab. Once a tumor cell line is resistant to Trastuzumab, an anti-HER2, it is automatically resistant to Pertuzumab as well. This is because both of these drugs work in the same way, with the same goal: binding to different units of the HER2 receptor to inhibit its ligand-independent mitogenic signaling. Thus once a tumor is resistant to one anti-HER2 it is my guess, that it is resistant to the secondary anti-HER2 as well.
This however needs to be supported by clinical trials to have substantial evidence for the effect of Pertuzumab on metastatic tumors that are relapsed.

In conclusion, Pertuzumab is then not the solution to relapsed tumor Herceptin resistance. It is an effective drug to be used in conjuction with Herceptin to generally improve patient prognosis.

The following papers do not have online links but can be found in the dropbox:
2* Baselga, Jose et al. "Pertuzumab plus Trastuzumab plus Docetaxel for Metastatic Breast Cancer". 2012.
3* Baselga, Jose and Swain, Sandra M. "CLEOPATRA: A Phase III Evaluation of Pertuzumab and Trastuzumab for HER2-Positive Metastatic Breast Cancer". 2010.