June 1, 2018
Over the past twenty years significant progress has been made in the detection and treatment of breast cancer. In fact, many women who now present with early stage disease have excellent outcomes due to improved therapy. One of the most significant findings over the past decade has been the realization that breast cancer is a heterogeneous disease. This helps explain why some women benefit greatly from current therapies whereas other women benefit less and some seem to be resistant to treatment altogether. It also suggests that in order to achieve the best results for patients we need the ability to provide personalized treatments that are tailored to an individual patient based on that patient’s particular tumor profile.
The development and use of Herceptin®, a drug that effectively targets a particular type of breast cancer tumor (HER2+), is an excellent example of advances in tailoring breast cancer treatment to biology. Herceptin® has been an extremely important addition to the breast cancer treatment arsenal.
However, we need many more “Herceptins” in our toolkit if we are to effectively treat the many forms of breast cancer. And we cannot afford the ten to twenty years it takes for a traditional trial to yield a successful drug, as it took for Herceptin®. If we are going to be able to develop more personalized treatments in an accelerated timeframe, we need to develop a new type of clinical trial. Specifically, we need to be able to:
And that is precisely what we have done with The I-SPY TRIAL Program.
Designed to be a national resource, The I-SPY TRIAL (Investigation of Serial Studies to PredictYour Therapeutic Response with Imaging And moLecular Analysis or I-SPY 1) is a collaboration between the National Cancer Institute and ten cancer centers across the country.
I-SPY 1 involved serial imaging and tissue collection for women with tumors at least 3 centimeters in size who underwent neoadjuvant therapy. Neoadjuvant therapy is chemotherapy given prior to surgery. Neoadjuvant therapy has the advantage of allowing us to actually see the tumor’s response to treatment before we remove it, and thus is the ideal platform to identify mechanisms of resistance, develop diagnostic indicators, and individualize therapy. More traditional drug development processes utilize adjuvant trials and require long follow-up, many thousands of patients, and may take ten to twenty years to go from laboratory bench to patient bedside. Moreover, substantial investment in time and resources is also required to identify drugs that will fail. In contrast, the neoadjuvant setting provides a forum to rapidly design and test new treatment strategies.
The main objective of the I-SPY 1 TRIAL was to identify indicators of response to neoadjuvant chemotherapy that predict survival in women with high-risk (Stage II-III) breast cancer. For example, one goal was to determine if there was a correlation between a Magnetic Resonance Imaging (MRI) depiction of a tumor decreasing in volume after administering neoadjuvant chemotherapy and long term survival/recurrence. A total of 237 participants were enrolled over a four-year period ending in March 2006. We amended the protocol to enroll an additional 100 to 140 participants. The amended I-SPY 1 protocol was re-opened in August 2007. A total of 78 additional participants have been enrolled to date. We anticipate that we will enroll a total of 100 participants by December 2009.
Certain principles were agreed upon at the onset of the trial. Investigators consented:
These principles allowed us to recruit investigators from multiple institutions and engage them in the very important work of rapidly translating tissue and imaging markers/indicators into improved clinical care.
Molecular profiles predicted the response of the tumors to chemotherapy drugs.
We also found that most locally advanced breast cancers are discovered in the interval between routine mammogram exams, typically conducted every one or two years. Of the women participating in the trial who underwent regular screening mammograms, 83 percent were diagnosed with breast cancer outside their regular screenings. This finding suggests the effectiveness of early detection of locally advanced breast cancer by conventional screening is hindered by the fast growth rate of this type of breast cancer.On the basis of these findings we are now ready to take the next step.
I-SPY 2 is the logical and innovative evolution of the I-SPY TRIAL program. In the course of this trial we will identify women at highest risk and introduce the most promising drugs in development that are individually targeted to the characteristics of each woman’s tumor. The purpose of the study is to further advance our ability to practice personalized medicine by:
There are four key transformative concepts in I-SPY 2:
As with its predecessor, I-SPY 2 is focused on collaboration across institutions. Collaboration in I-SPY 2 includes the FDA, the National Cancer Institute (NCI), the Foundation for the National Institutes of Health (FNIH) Biomarker’s Consortium, at least 11 leading academic centers (researchers and physicians), major pharmaceutical companies and breast cancer patient advocates. It involves investigators sharing data, tissue, tools, and common information management platforms and repositories. A sophisticated informatics portal has been built to integrate and interpret the complex and disparate data (genomics, proteomics, pathology, and imaging) from many investigators, providing real-time access to study data for effective adaptation in the trial.
Given the highly motivated and expert I-SPY 2 team, existing infrastructure from the original I-SPYTRIAL, adaptive trial design, existing and developing biomarkers, promising investigational cancer drugs, and the use of early endpoints to learn what works within months rather than years, this initiative promises to be transformational for women with breast cancer.
Rev. July 31, 2009