Pathologic Complete Response: How may the I-SPY2 trial help HR positive HER2 negative Breast Cancer patients? Laura Huppert
By Laura Huppert, MD
The I-SPY2 trial is a neoadjuvant phase 2 study that enrolls patients with any type of breast cancer who have a tumor at least 2.5 centimeters in size, and they’re randomized to receive the control, which is neoadjuvant Paclitaxel, followed by AC versus an investigational agent followed by AC. And then the primary endpoint of the study is pathologic complete response rate, or PCR (pathologic complete response). And in this study we basically wanted to look at, there were a thousand patients that were the first thousand patients on the I-SPY2 trial, and we wanted to look at the patients that had hormone receptor positive HER2 negative disease, and look at the PCR (pathologic complete response) rates, by clinical and molecular features. So specifically we were interested in the clinical features of stage and histology and the molecular features of whether they were MammaPrint high 1 or high 2. So we took the MammaPrint score and the lower end of the high score or the higher end of the high score and did that matter? We also looked at whether they were basal or luminal subtype and then also whether they had the response, predictive subtype, immune positive signature which I can describe a little bit more later. And so in this study we found that patients that had stage 2 disease had higher rates of PCR (pathologic complete response) than stage 3, which we might expect.
Patients who had ductal histology had slightly higher rates than patients with lobular or mixed histology. And then I think the most interesting finding is that looking at the MammaPrint and luminal basal distinctions, looking at the molecular features. So we found that patients who had MammaPrint high 1 disease so the lower end of the high score had lower rates of PCR (pathologic complete response) in the 10 to 15% range, and across most of the treatment arms versus the higher end of the MammaPrint, the high 2 had MammaPrint or had PCR (pathologic complete response) rates in the 31 to 34%, so its statistical significance is higher PCR (pathologic complete response) rates if they were in the higher end of the MammaPrint score. And similarly patients who had the luminal subtype had lower rates of PCR (pathologic complete response) versus those that had the basal subtype had much higher rates of PCR (pathologic complete response). And then finally we looked at the response, predictive subtype, immune signature. So my colleagues Christina Yao and Denise Wolf published a really elegant paper where they took different subtypes of breast cancer and further divided them by their molecular subtypes to create these response predictive subtypes that better predicted PCR (pathologic complete response) that are classical hormone receptor positive HER2 negative triple negative subtypes. And one of the subtypes they found in the hormone receptor positive group was whether it was immune positive or negative. And so when we looked at the patients in our cohort who were immune positive the rates of PCR (pathologic complete response) were substantially higher than those who are immune negative. Particularly in the patients in the pembrolizumab arm, the PCR (pathologic complete response) rate was greater than 60% if they were immune positive versus only 4% if they were immune negative.
So I think the takeaways from this study is that among patients with hormone receptor positive, HER2 negative breast cancer, it’s a very heterogeneous group. And so some patients tend to respond better and some patients tend to respond worse. And traditionally we’ve grouped these patients all together and given them the same treatment. But in fact, I think there are very distinct subtypes. There are patients with higher risk disease, lower risk disease that will respond better or worse to neoadjuvant therapy. And so by breaking these patients down, by breaking their them down by the different molecular pattern, we can really better predict who’s gonna respond and ideally in the future, tailor their treatment to based on these response predictive subtypes and molecular features.
Will The Data on the I-SPY2 Clinical Trial Affect Clinicians Today?
So I think in terms of whether this data will affect clinicians today at this point it’s relatively hypothesis generating, so I don’t think it’s going to change treatment tomorrow per se, but I do think that the concepts are potentially gonna change are the way we practice treatment of breast cancer in the future. Because I do think that if we can better distinguish subtypes of breast cancer by these molecular features, we’ll be able to better treat patients by pairing, their breast cancer biology with the best treatment. And so really have a more biologically based and individualized treatment approach.
And one of the really interesting things we’re doing in the I-SPY2 study is we’re actually this month rolling out I-SPY2.2, which rather than just randomizing patients based on whether they’re ER positive HER2 postive triple negative. We’re using these response predictive subtypes to better randomize patients, basically based on the biology of their disease. And that’ll help hopefully it’ll better predict PCR (pathologic complete response) rates. So we’re gonna put the work from this study and several others in the I-SPY group into action in prospectively look at it in the I-SPY 2.2 study.
I think in closing, the most exciting aspects of this data are that we are better able to break down hormone receptor positive HER2 negative breast cancer into these distinct subtypes that respond better or worse to neoadjuvant therapy. And I think we need to study this more and understand. Which patients will benefit most from neoadjuvant treatment because hopefully we can better classify hormone receptor positive HER2 negative breast cancer to individualize treatment for these patients based on biology to improve outcomes for this really heterogeneous group of patients. Laura Huppert, MD
What is Pathologic Complete Response?
Pathologic complete response (pCR) is a term used to describe the absence of invasive cancer cells in the breast and lymph nodes after neoadjuvant chemotherapy (NAC) treatment for breast cancer. Achieving pCR has been associated with better long-term outcomes, such as a lower risk of cancer recurrence and improved survival rates.
Studies have shown that patients who achieve pCR after NAC have a better prognosis than those who do not. However, not all patients respond equally to NAC, and factors such as tumor subtype, hormone receptor status, and age can affect the likelihood of achieving pCR.
The use of pCR as a primary endpoint in clinical trials has been debated. While pCR has been shown to be a good predictor of long-term outcomes, it is not a guarantee of success. Some researchers argue that other endpoints, such as event-free survival and overall survival, should also be considered in clinical trials.
In conclusion, pCR is an important measure of response to NAC in breast cancer. While achieving pCR is associated with improved long-term outcomes, it is not a guarantee of success, and other factors should be considered in the evaluation of new treatments for breast cancer.
10 Key Takeaways on the I-SPY2 Clinical Trial
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The I-SPY2 Trial is a phase II clinical trial that aims to test the effectiveness of new drugs for the treatment of breast cancer.
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The trial is designed to use an adaptive platform to test multiple drugs simultaneously, allowing for a faster and more efficient evaluation of potential treatments.
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The primary endpoint of the trial is pathologic complete response (pCR), which is defined as the absence of residual cancer in the breast and lymph nodes after neoadjuvant therapy.
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The trial uses a novel statistical method called Bayesian probability to determine the probability of success for each drug, which helps to prioritize the most promising treatments for further study.
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The trial includes multiple biomarker-driven sub-studies, which allow for a more personalized approach to treatment based on the patient’s individual tumor characteristics.
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One of the most promising drugs identified in the trial is pembrolizumab, an immune checkpoint inhibitor that has been shown to increase pCR rates in patients with aggressive breast cancer.
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The trial has demonstrated that the use of neoadjuvant therapy can significantly improve pCR rates and increase the likelihood of breast-conserving surgery.
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The trial has also shown that the addition of targeted therapies to standard chemotherapy can improve pCR rates and may lead to better long-term outcomes for patients.
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The I-SPY2 Trial has established a new standard for clinical trial design and has paved the way for more efficient and effective drug development in breast cancer and other cancers like HER2 positive, early stage breast cancer, and metastatic breast cancer.
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The success of the I-SPY2 Trial highlights the importance of collaboration between academia, industry, and regulatory agencies in advancing cancer research and improving patient outcomes.
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What was surprising about the I-SPY2 Clinical Pathologic Complete Response?
The most surprising thing about the I-SPY2 Clinical Pathologic Complete Response (pCR) is the remarkable success of the adaptive trial design. The I-SPY2 trial is a groundbreaking clinical trial for breast cancer patients that aims to identify the most effective treatments for each patient’s specific tumor type.
One of the trial’s primary endpoints is to achieve a pathologic complete response (pCR), which means there is no evidence of residual cancer in the breast tissue and lymph nodes following neoadjuvant (pre-surgical) therapy. The I-SPY2 trial uses an innovative adaptive trial design that enables researchers to test multiple drugs simultaneously, accelerate the pace of drug discovery, and increase the probability of success.
The most surprising finding from the I-SPY2 trial is the high rate of pCR achieved in patients treated with some of the experimental drugs. For example, the trial showed that the combination of the drug pembrolizumab with standard chemotherapy resulted in a pCR rate of 64%, which is significantly higher than the historical pCR rate of 20-30% for standard chemotherapy alone. Additionally, other experimental drugs tested in the trial have also shown impressive results, including the drugs veliparib and neratinib.
These findings are significant because they provide hope for breast cancer patients who have historically had limited treatment options. The I-SPY2 trial’s adaptive trial design has enabled researchers to quickly identify the most promising treatments for specific subtypes of breast cancer and has already led to FDA approval for some of the experimental drugs.
In summary, the most surprising thing about the I-SPY2 Clinical Pathologic Complete Response is the remarkable success of the adaptive trial design, which has led to the identification of effective treatments for breast cancer patients and accelerated the pace of drug discovery and follow up.
Laura Huppert, MD – About The Author, Credentials, and Affiliations
Laura Huppert, MD, is an accomplished in medical oncology specializing in the treatment of breast cancer patients across all stages of the disease. Her research primarily focuses on clinical trials aimed at evaluating new cancer treatments and innovative ways to combine therapies to improve patient outcomes. Additionally, Dr. Huppert’s work centers on metastatic breast cancer, including cases that have spread to the brain and leptomeninges. She actively seeks to translate laboratory discoveries into practical and effective care for her patients in medical oncology.
Dr. Huppert earned her medical degree from Harvard Medical School and subsequently completed her residency in internal medicine and a fellowship in hematology and oncology at the University of California, San Francisco. She is an esteemed member of the American Society of Clinical Oncology (ASCO) and has been recognized for her contributions to the field with an ASCO Merit Award and grants from the California Breast Cancer Research Program.