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…
“In patients with metastatic triple negative breast cancer (TNBC), turning a nonimmunogenic (“cold”) tumor into an immunogenic (“hot”) tumor appears to be feasible, thereby improving sensitivity to immune therapy with nivolumab (Opdivo).
“In a phase II study of 50 patients with metastatic TNBC who received palliative chemotherapy, priming the immune system with low-dose chemotherapy for 2 weeks or radiation therapy before starting nivolumab resulted in a best objective response rate (ORR) of 24%, announced Marleen Kok, MD, at the 2017 ESMO Congress in Madrid.”
“The randomized phase II LOTUS trial has shown improved progression-free survival with the addition of the AKT inhibitor ipatasertib to paclitaxel in the first-line treatment of metastatic triple-negative breast cancer. These results were reported by Kim et al in The Lancet Oncology. The PI3K/AKT signaling pathway is frequently activated in triple-negative breast cancer.
“In the double-blind trial, 124 patients with unresectable locally advanced or metastatic disease from 44 sites in South Korea, the United States, France, Spain, Taiwan, Singapore, Italy, and Belgium were randomized between September 2014 and February 2016 to receive paclitaxel at 80 mg/m² on days 1, 8, and 15 with either ipatasertib at 400 mg (n = 62) or placebo (n = 62) once daily on days 1 to 21 every 28 days until disease progression or unacceptable toxicity. Stratification factors included tumor PTEN status as determined by immunohistochemistry; deficient expression of PTEN is associated with greater AKT pathway activation. The co-primary endpoints were progression-free survival in the intention-to-treat population and progression-free survival in the PTEN-low population.”
“Sacituzumab govitecan (IMMU-132) was well tolerated and demonstrated early and durable responses in heavily pretreated patients with metastatic triple-negative breast cancer (mTNBC), according to the results of a recent phase I/II study published in the Journal of Clinical Oncology.
“Sacituzumab govitecan is an antibody–drug conjugate that targets Trop-2, which is expressed in more than 90% of TNBCs, by selectively delivering SN-38, the active metabolite of irinotecan. It was granted a breakthrough therapy designation by the FDA in February 2016 for the treatment of patients with mTNBC, following at least 2 treatments for metastatic disease.”
“With the prospect of phase III data that could confirm their efficacy, checkpoint inhibitors against PD-1 and PD-L1 have shown promise, both as monotherapies and in combination with chemotherapy for patients with triple-negative breast cancer (TNBC), Sylvia Adams, MD, said during a presentation at the 16th Annual International Congress on the Future of Breast Cancer East.
” ‘We think there is definitely value for immune checkpoint blockade in triple-negative disease. When you look at the metastatic trials, while the response rates are relatively low, most of the responses are durable,’ said Adams, from the NYU Langone Medical Center. ‘For patient selection, it is important to consider the line of therapy. The earlier the better.’ ”
Last month, the annual American Society of Clinical Oncology (ASCO) meeting took place in Chicago. Thousands of oncologists, patients, and journalists gathered to learn about the most recent developments in cancer research and treatment. Here are some breast cancer highlights from the meeting:
Triple negative breast cancer (TNBC) is considered more responsive to treatment with immune checkpoint drugs than any other type of breast cancer. So far, these drugs have primarily been explored in metastatic TNBC, in combination with chemotherapy. The combination of “anti-PD-L1” and “anti-PD-1” immune checkpoint drugs with chemotherapy has now been examined in early-stage TNBC, in which a breast tumor can be surgically removed after neoadjuvant chemotherapy. Continue reading…
“In patients with heavily pretreated metastatic triple-negative breast cancer (TNBC), pembrolizumab (Keytruda) showed durable antitumor activity, according to findings from cohort A of the phase II KEYNOTE-086 trial presented at the 2017 ASCO Annual Meeting.
“The overall response rate (ORR) was 4.7% (95% CI, 2.3-9.2) with single-agent pembrolizumab, including a complete response (CR) rate of 0.6% and a partial response (PR) rate of 4.1%. The stable disease (SD) rate was 20.6%. The median duration of response was 6.3 months (range, 1.2+ to 10.3+).”
“At the 2017 ASCO Annual Meeting, results were presented from the phase II I-SPY 2 trial investigating pembrolizumab (Keytruda) in combination with standard therapy (paclitaxel followed by doxorubicin and cyclophosphamide) as a neoadjuvant treatment for patients with locally advanced triple-negative breast cancer or hormone receptor–positive/HER2-negative breast cancer (Abstract 506).
“Findings showed that the addition of pembrolizumab increased the estimated pathologic complete response rate nearly threefold in patients with triple-negative breast cancer (60% vs 20%) and in patients with hormone receptor–positive/HER2-negative breast cancer (34% vs 13%) compared to standard therapy. Overall, based on Bayesian predictive probability of success in a confirmatory phase III trial, pembrolizumab has graduated from the I-SPY 2 TRIAL for all signatures in which it was tested (triple-negative breast cancer, all HER2-negative, and hormone receptor–positive/HER2-negative).”
“According to the results of a phase I study of single agent anti-PD-L1 atezolizumab (Tecentriq) in metastatic triple-negative breast cancer (mTNBC), ten percent of patients showed impressive long-term survival, although researchers said that aside from some biomarker evidence, it’s yet unclear why the drug was more effective in this subset of patients.
“Results of the study were presented this week at the AACR Annual Meeting 2017 by lead author Peter Schmid, MD, PhD, director of the St. Bartholomew’s Breast Centre at St. Bartholomew’s Hospital and Barts Cancer Institute in London.”