What is neoadjuvant therapy for breast cancer?
Neoadjuvant therapy for breast cancer has unique advantages, such as allowing resection of otherwise unresectable tumors, reducing the stage of locally advanced breast cancer, increasing the chance of breast-conserving surgery, serving as a platform for rapid evaluation of traditional anti-cancer drugs and new targeted agents, and studying residual lesions after neoadjuvant therapy to further refine individualized treatment plans.
Professor Dimitrios Zardavas from Belgium, in an article published in the Annual Review of Medicine in October 2014, reviewed the results of breast cancer research to date.
in an article published in October 2014 in the Annual Review of Medicine, provides a comprehensive review of neoadjuvant breast cancer therapies to date.
Neoadjuvant chemotherapy
Currently, most randomized clinical trial studies of anthracycline-based neoadjuvant chemotherapy have shown that neoadjuvant therapy is not significantly different from conventional therapy. Although some individual studies point to a slightly higher rate of local recurrence with neoadjuvant therapy, it is not statistically significant.
As for the addition of paclitaxel-like compounds to anthracycline regimens, the limited studies available suggest better clinical outcomes and pathological remission rates, but this advantage is not statistically significant. The incorporation of other chemotherapeutic agents such as capecitabine and gemcitabine into anthracycline- or paclitaxel-based neoadjuvant chemotherapy regimens did not show significant advantages in terms of pathologic remission rates or odds of breast-conserving surgery.
These results suggest that neoadjuvant chemotherapy based on anthracyclines or paclitaxel should be considered as the standard regimen for neoadjuvant breast cancer treatment.
Neoadjuvant hormonal therapy
Neoadjuvant hormonal therapy using aromatase inhibitors is increasingly being used in primary breast cancer in estrogen receptor-positive, HER2-negative menopausal women. Most of the clinical trials comparing aromatase inhibitors with triamcinolone have been conducted in menopausal women and have shown superior results with aromatase inhibitors over triamcinolone.
The only randomized study comparing aromatase inhibitors with triamcinolone as neoadjuvant hormonal therapy in premenopausal breast cancer patients (STAGE) demonstrated significantly higher objective clinical effectiveness and response rates as assessed by ultrasound or magnetic resonance with anastrozole.
Neoadjuvant HER2 blockade therapy
The main conclusion of the initial trials for trastuzumab, all aimed at assessing the efficacy of the drug in combination with different chemotherapeutic agents, was that trastuzumab in combination with neoadjuvant chemotherapy could improve antitumor activity, with a reported 12-76% increase in pathological complete remission. On this basis, randomized trials on neoadjuvant chemotherapy with trastuzumab have shown significant benefits in terms of disease-free survival and pathologic complete remission rates with the addition of trastuzumab.
HER2 double blockade neoadjuvant therapy
Despite the significant antitumor effect of trastuzumab in combination with cytotoxic chemotherapy in HER2-positive breast cancer, drug resistance remains a problem and further treatment options are therefore needed.
One promising approach is dual blockade adjuvant therapy with HER2, where different HER2-targeting agents with complementary effects are combined. Trastuzumab is the main component of HER2 dual blockade adjuvant therapy, to which a small molecule reversible epidermal growth factor receptor (EGFR)/HER2 tyrosine kinase inhibitor, lapatinib, or a humanized anti-HER2 monoclonal antibody, such as patuximab, is added to block the dimerization of HER2 with other HER2 family receptors. .
Important takeaways from clinical trials targeting such regimens are summarized below.
HER2 dual blockade has a high rate of complete remission of pathology.
HER2 double blockade can be safely combined with cytotoxic chemotherapy.
HER2 double blockade can also achieve high rates of pathologic complete remission in hormone receptor-negative, HER2-positive breast cancer patients.
Some HER2-positive breast cancer patients achieve complete remission without cytotoxic chemotherapy and with HER2 double blockade, which means that some patients may be spared the side effects of chemotherapy.
The results reflect the biological significance of the HER2 signaling pathway in this subset of breast cancer patients, as longer duration of HER2 double blockade may result in higher rates of complete remission.
Trastuzumab, patuximab, and lapatinib are similarly effective in neoadjuvant therapy when used in single combination with cytotoxic chemotherapeutic agents. However, there are no trials designed to address this issue.
Other molecularly targeted agents in neoadjuvant therapy
For this problem, studies are currently focused on monoclonal antibodies to vascular endothelial growth factor A, namely bevacizumab. For its neoadjuvant treatment, there have been a large number of phase II randomized trials and some phase III randomized trials. The results suggest that bevacizumab significantly increases the rate of pathologic complete remission in at least hormone receptor-positive, HER2-negative breast cancer patients. Of course, there are also studies showing the same beneficial effect of bevacizumab on complete pathologic remission in the hormone receptor-negative patient group. Given the side effects of the drug (e.g., hypertension, mucositis, etc.) and its controversial effects in different types of breast cancer, numerous, rigorous clinical trials are currently underway.
Several blockers targeting the PI3K/AKT/mTOR signaling pathway are also undergoing clinical studies. There is substantial evidence that PI3K pathway activation is associated with the regulation of drug resistance in endocrine therapy and HER2 blockade therapy for breast cancer. The fastest studied class of PI3K blockers, rapamycin analogs, and everolimus have received U.S. Food and Drug Administration (FDA) clearance for the treatment of hormone-resistant metastatic breast cancer. Today, all three major types of breast cancer (ductal, triple negative, and HER2-positive) are in clinical trials for neoadjuvant therapy.
Alternative indicators in neoadjuvant therapy
Neoadjuvant therapy offers an opportunity to quickly assess the efficacy of anticancer drugs by certain short-term indicators related to long-term clinical prognosis. The FDA issued a draft guideline in May 2012 that is a non-mandatory recommendation for expediting approval of novel agents for patients with high-risk breast cancer based on surrogate indicators that predict long-term clinical prognosis.
Pathologic complete remission is one such surrogate, but the relationship between this indicator and long-term clinical outcomes is somewhat controversial. This is partly due to methodological limitations arising from the different definitions of pathologic complete remission in different studies, and partly probably due to the different types of breast cancer. In neoadjuvant hormonal therapy, Ki-67 levels on treatment are considered as a potential biological marker of prognosis.
Neoadjuvant therapy trials as a clinical research tool
Neoadjuvant therapy in breast cancer is increasingly recognized as an effective clinical development platform for new anti-cancer drugs, for example, as a rapidly evolving arsenal of targeted breast cancer drug trials. Neoadjuvant therapies are interspersed with tumor biopsies thus allowing the opportunity for in vivo evaluation. The study of residual breast cancer after neoadjuvant therapy represents another important research opportunity.
The window of opportunity trial is a novel experimental design recently introduced in oncology. In such trials, patients are treated with a compound under investigation during a window of opportunity prior to receiving anticancer therapy. Such trials can assess the biological effects of the complex under study by molecular analysis of the tumor or by functional imaging. Such trials have evaluated the biological effects of metformin and erlotinib (an anti-EGFR drug). There have also been studies of window of opportunity trials with trastuzumab, lapatinib, or a combination of both.
Conclusion
Neoadjuvant therapies are emerging and are being used as a therapeutic platform for patients with metastasis-free breast cancer, especially in cases with inoperable tumors or where breast conservation is the treatment goal.
For neoadjuvant chemotherapy, patients with triple-negative breast cancer or overall highly proliferative tumors have high rates of pathologic complete remission. For HER2
positive breast cancer, the addition of trastuzumab to neoadjuvant chemotherapy improved pathologic complete remission rates, and clinical evaluation concluded that the HER2 dual blockade strategy doubled pathologic complete remission rates. In the case of hormone receptor-positive breast cancer, neoadjuvant hormonal therapy has a high risk ratio.
Given the therapeutic potential of neoadjuvant therapy and the associated research opportunities, it has been proposed that it can be recommended for all patients with early-stage breast cancer. Different surrogate indicators, such as pathological complete remission rates in neoadjuvant chemotherapy and Ki-67 levels in neoadjuvant hormonal therapy, can predict the long-term clinical prognosis of breast cancer patients in neoadjuvant therapy, thus further facilitating the clinical development of novel anticancer agents.
It is also becoming increasingly clear that the neoadjuvant platform offers unique research opportunities to elucidate the biological role of targeted agents in vivo, identify predictive biological markers of sensitivity and/or resistance, and ultimately screen patients with a high chance of recurrence for evaluation of investigational agents.