Non-metastatic breast cancers are most often treated with surgery, but if the tumors are fairly large, or involve nearby lymph nodes, neoadjuvant (pre-operative) treatments with chemotherapy (NAC) are done first. NAC often reduces the tumor size and kills cancer cells in lymph nodes, if present, prior to surgery, improving the outcome. The best possible result of neoadjuvant treatment is pCR (pathologic compete response), when the tumor is no longer visible in imaging studies. Here, I review the new directions in which neoadjuvant treatments are evolving.
Today, treatments for metastatic breast cancers are tailored for specific subtypes. Starting with the introduction of the drug trastuzumab (Herceptin) for HER2-positive cancers, new, more specific treatment options were eventually developed and approved for other types as well. Estrogen deprivation endocrine therapies, lately prescribed in combination with CDK4/6 inhibitors, are used in estrogen receptor (ER)-positive cancers. Triple negative cancers (TNBC) are still treated mostly with chemotherapy, but immune checkpoint drugs and PARP inhibitors are explored in clinical trials, with some successes reported.
However, neoadjuvant treatments (except for HER2+ cancers) remain largely limited to chemotherapy regimens. This is starting to change now, with new approaches tailored to the cancer type being investigated in clinical trials.
In this regard, it is important to mention the I-SPY2 trial, NCT01042379, which started in 2010 and is for women with stage II-III breast cancer. It offers about a dozen drugs that are chosen based on particular features of the newly diagnosed cancers. This trial has a unique design and has produced some important results. Additional treatments and trials for various types of breast cancer are discussed below. Continue reading…
“Being diagnosed with a malignant brain tumor is devastating news for patients and their loved ones. Whereas some types of tumor respond well to treatment, others such as glioblastomas – the most common and aggressive brain tumors – are known to recur and progress within short times from the diagnosis. Patients diagnosed with this type of cancer, and who undergo current standard treatment, have a median survival of 16 months.
Based on recent information on the mechanisms of chemotherapy, a team of researchers of the McGill University Health Centre (MUHC) developed a new clinical approach to increase the efficiency of treatment in glioblastomas that increased the median survival to 22 months – bringing much needed hope to those affected by this aggressive disease. The findings of this promising phase II clinical trial have been published in the International Journal of Radiology Oncology.”
“Neoadjuvant endocrine therapy – designed to reduce the size of breast tumors before surgical removal – appears to be as effective as neoadjuvant chemotherapy for patients with localized, estrogen-receptor (ER)-positive breast cancer with considerably fewer side effects. The study conducted by a Massachusetts General Hospital (MGH) Cancer Center research team appears in the current print issue of JAMA Oncology and was published online earlier this year.”
“Women with lymph node-positive breast cancer who demonstrate complete nodal response by axillary ultrasound after neoadjuvant chemotherapy may be able to avoid axillary dissection, according to study results.
“ ‘Our goal here is really to try to get away from, “Every patient with breast cancer needs these drugs and this amount of chemotherapy and surgery,” and instead to personalize surgical treatment based on how the patient responds to chemotherapy,’ Judy Boughey, MD, chair of the division of surgery research at Mayo Clinic in Rochester, Minnesota, said in a press release.
“The American College of Surgeons Oncology Group (ACOSOG) Z1071 trial included 687 patients with T0-4, N1-2, M0 primary invasive breast cancer. All patients completed neoadjuvant chemotherapy, underwent sentinel lymph node surgery and axillary dissection, and had axillary ultrasound images available for review.
“Previously published results indicated a 12.6% false-negative rate for sentinel lymph node surgery after neoadjuvant chemotherapy for patients who presented with node-positive disease and had two or more sentinel lymph nodes identified and removed. This false-negative rate exceeded the predetermined acceptable rate of 10%. The result suggested patient selection or technique must be improved prior to widespread adoption of sentinel lymph node surgery in this setting, according to study background…
“ ‘That’s one of the really nice things about giving chemotherapy up front,’ Boughey said. ‘It allows us to be less invasive with surgery, both in terms of breast surgery and lymph node surgery, and to tailor treatment based on response to chemotherapy.’ “
“Patients with larger malignant tumors of the breast who undergo chemotherapy before a breast cancer operation are more likely to undergo a lumpectomy than a mastectomy, according to a study published by Killelea et al in the Journal of the American College of Surgeons.
“ ‘Going forward, it will be interesting to see whether or not the use of neoadjuvant therapy continues to rise as newer drugs and agents are being developed all the time,’ Dr. Killelea said. ‘It will also be interesting to watch what happens to the rate of breast conservation over time. We don’t know. That’s why it’s so important for us to have a database like NCDB.’ ”
“Patients with larger malignant tumors of the breast who undergo chemotherapy before a breast cancer operation are more likely to opt for a breast-preserving procedure and forgo a mastectomy (surgical removal of the breast), according to a new study published online as an “article in press” in the journal of the american college of surgeons. the study will appear in a print edition of the Journal this spring.
“Study investigators from Yale University School of Medicine and Yale University Comprehensive Cancer Center, New Haven, Conn. also determined that rates of chemotherapy before breast operations, known as neoadjuvant therapy, had increased significantly through the five-year study period, possibly because the FDA had approved better chemotherapy drugs.
“Lead investigator general surgeon, Brigid K. Killelea, MD, MPH, FACS, called the study results ‘very exciting.’ It is one of the largest studies to date on the use of chemotherapy before surgical treatment for breast cancer.
” ‘We’ve seen data published from clinical trials showing that neoadjuvant chemotherapy results in increased lumpectomy rates but this is really one of the first studies using a large national database that reflects what is also going on in the community hospital setting,’ she said. (During a lumpectomy procedure only the tumor and surrounding tissue is removed, leaving the rest of the breast tissue intact.)”
The gist: Many women with HER2-positive breast cancer take the drug trastuzumab (aka Herceptin) along with chemotherapy after tumor-removal surgery to keep the cancer from returning. However, new research shows that women who have high levels of certain immune system cells in their tumors might not benefit from Herceptin. For these patients, chemotherapy might be just as effective at preventing the return of cancer as the chemo/Herceptin combo.
“HER2-positive breast cancers with a high level of immune cell infiltration might not benefit from the addition of trastuzumab (Herceptin) to chemotherapy, a trial analysis suggested.
“The 10% of patients with stromal tumor-infiltrating lymphocyte-predominant breast cancer in the Alliance N9831 trial showed similar recurrence-free survival (RFS) whether they received chemotherapy alone or with trastuzumab (10-year rate 90.9% versus 80.0%,P=0.21), Edith A. Perez, MD, of the Mayo Clinic in Jacksonville, Fla., and colleagues found.
“The rest showed, as expected, significantly better recurrence-free survival with addition of trastuzumab (10-year rate 79.6% versus 64.3%, hazard ratio 0.49, P=0.0003), they reported here at the San Antonio Breast Cancer Symposium.”
The gist: A new drug called PLX3397 will now be available through the innovative I-SPY 2clinical trial, which uses molecular testing to match breast cancer patients to the pre-surgery treatments most likely to work for them. The trial is open for participation by women with newly diagnosed, locally advanced breast cancer.
“Plexxikon Inc., a member of Daiichi Sankyo Group, and QuantumLeap Healthcare Collaborative today announced that Plexxikon’s drug candidate, PLX3397, has been selected for study in the I-SPY 2 TRIAL (Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging And moLecular Analysis 2). I-SPY 2 is a standing phase 2 randomized, controlled, multicenter trial for women with newly diagnosed, locally advanced breast cancer (minimum of Stage 2) that is designed to test whether adding investigational drugs to standard chemotherapy is better than standard chemotherapy alone in the neoadjuvant setting (prior to surgery).
“I-SPY 2 is conducted by a consortium that brings together the Food and Drug Administration (FDA), National Cancer Institute (NCI), pharmaceutical companies, leading academic medical centers, and patient advocacy groups under its umbrella. The trial is sponsored by QuantumLeap Healthcare Collaborative (QLHC), a 501(c)(3) non-profit organization dedicated to accelerating healthcare solutions.
“The I-SPY 2 TRIAL employs a unique adaptive trial design to match experimental therapies with patients. Genetic or biological markers (‘biomarkers’) from individual patients’ tumors are used to screen promising new treatments, identifying which therapies are most effective in specific patient subgroups. Regimens that have a high Bayesian predictive probability of showing superiority in a 300 patient phase 3 confirmatory trial in at least one of 10 predefined signatures may ‘graduate’ from I-SPY. This high efficacy bar and rapid turnaround time allows the trial to identify the right drug for the right patient in the most expeditious fashion.”
The gist: Women with basal-like triple-negative breast cancer (TNBC) might benefit from adding either the drug bevacizumab (Avastin) or the drug carboplatin to their chemotherapy treatment before tumor-removal surgery (neoadjuvant chemotherapy). For non-basal-like TNBC patients, carboplatin shows similar benefit, but bevacizumab may actually worsen their treatment response.
“A study of women with triple-negative breast cancer (TNBC) has shown that women with the basal-like subtype of breast cancer had higher rates of pathologic complete response (pCR) with the addition of bevacizumab (Avastin) to neoadjuvant chemotherapy than did women with non–basal-like breast cancer. No difference in response was seen between the two subtypes for the addition of carboplatin.
“These results were part of a subtype analysis of the CALGB/Alliance 40603 study and were presented at the 2014 San Antonio Breast Cancer Symposium, held December 9–13 in San Antonio, Texas, by William M. Sikov, MD, associate director of clinical research for the program in women’s oncology at Women and Infants Hospital and associate professor of medicine at Alpert Medical School of Brown University in Providence, Rhode Island.
“Earlier this year, results of the initial study of 443 women published in the Journal of Clinical Oncology showed that the addition of carboplatin or bevacizumab to neoadjuvant chemotherapy in women with stage II to III TNBC increased rates of pCR. In the subtype analysis, Sikov and colleagues sought to identify subgroups of patients who were more or less likely to benefit from the addition of these therapies.