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.
ER+ breast cancers
The new trend for this major type of breast cancer is to try and replace neoadjuvant chemotherapy with endocrine (hormonal) or targeted drugs. Endocrine drugs that suppress estrogen signaling are almost always used to prevent recurrence after surgery. In new trials of neoadjuvant treatments for ER+ cancers, these drugs are combined with the CDK4/6 inhibitors palbociclib or ribociclib. The U.S. Food and Drug Administration (FDA) has now approved these drugs for treating metastatic ER+ cancers, and they may eventually replace chemotherapy before surgery. Other trials are exploring investigational drugs that inhibit key signaling pathways in cancer cells, such as the mTORC inhibitor TAK-228 or PI3K inhibitors, in addition to endocrine drugs.
The only trial of this kind that has reported results is LORELEI, which compared a combination of the aromatase inhibitor letrozole and the PI3K inhibitor taselisib with letrozole alone. The combination induced a higher rate of tumor shrinkage than the hormonal drug alone (50% versus 39%), but the rates of pCR were not different. I should note that the data would have been more significant if trial had compared the combination of letrozole and taselisib with chemotherapy as the current standard of treatment.
Other trials are exploring the immune checkpoint drug pembrolizumab (anti-PD-1) in neoadjuvant treatments in ER+ breast cancers even though this type is thought to be immunologically “cold;”i,e., not responsive to treatments that use the immune system to fight cancer. Chemotherapy is still part of the treatment in these trials, either before or along with pembrolizumab, but the immune drug may deepen the response, leading to pCR.
Inflammatory breast cancer is a particularly aggressive type that is encountered amongst ER+ (and other types) of breast cancers. There is often no or poor response to NAC seen in inflammatory cancers, and one of the two ongoing trials with pembrolizumab is attempting to determine if pembrolizumab combined with a hormonal drug may further shrink tumors after NAC is completed.
Immunotherapy combined with chemotherapy is actively being explored in trials and is considered to have promise in metastatic TNBC. No wonder that it is now being investigated in the neoadjuvant setting. The driving force for this is based on findings that immunotherapy with chemotherapy works much better in newly diagnosed metastatic TNBC patients than in those who have already received chemotherapy and recurred; it may work even better before surgery for earlier stages.
Several anti-PD-1 and anti-PD-L1 immune checkpoint drugs are currently in trials for stage I-III TNBC in combination with chemotherapy: pembrolizumab (anti-PD1), durvalumab (anti-PD-L1), and atezolizumab (anti-PD-L1). T-VEC, an immune system-stimulating drug of a different type that is injected directly into tumors, is FDA-approved for melanoma and is now being tested alongside chemotherapy as neoadjuvant therapy for TNBC (NCT02779855).
The high hopes for immune checkpoint drugs in neoadjuvant treatment are supported by the results of the ongoing I-SPY2 trial. In this trial, patients whose cancers (both ER- and ER+) were considered to be high risk received pembrolizumab in addition to the chemotherapy drug paclitaxel, followed by another chemotherapy regimen. Preliminary reports indicate that the pCR rate tripled in patients who received pembrolizumab.
There are also trials with other agents that have shown promise in metastatic TNBC, such as the PARP inhibitor talazoparib for BRCA-mutant cancers and mirvetuximab soravtansine aka IMG853 (an antibody-drug conjugate), a promising drug for cancers expressing a protein called folate receptor.
Some TNBCs express a protein called androgen receptor (AR) and may be treated with inhibitors of androgen signaling that are normally used for treatment of prostate cancers. This is also being tested in at least one trial.
For this type of breast cancer, NAC followed by a HER2-targeting drug is the standard of care. Trastuzumab (Herceptin) is FDA-approved in combination with NAC, and treatment with trastuzumab after surgery continues for a total of 12 months. Pertuzumab is an antibody drug that further inhibits HER2 by blocking its interactions with other “cancer enabling” proteins, and it is already FDA-approved along with trastuzumab and NAC.
The newer HER2-targeting agents—such as lapatinib, and T-DM1—are also introduced into the neoadjuvant setting. Lapatinib is a small-molecule inhibitor of HER2. T-DM1 is a version of trastuzumab “armed” with a cytotoxic (cell-killing) drug,.
In the ADAPT trial, T-DM1 given with an endocrine treatment showed a much higher activity in HER2+ cancers that are also ER+ than did trastuzumab with an endocrine drug. Perhaps the comparison was not quite fair because trastuzumab is always used in combination with chemotherapy in neoadjuvant treatment, and T-DM1 is in essence a targeted chemotherapy.
The table below lists clinical trials that are exploring new agents in neoadjuvant treatment:
|Trial||Type of breast cancer||Endocrine drug||Targeted drug||Immune drug||Chemotherapy||Comment|
|NCT01042379 I-SPY2||Any||–||various||pembrolizumab||various||Adaptive design|
|NCT03128619||ER+||Letrozole||PI3Ki Copanlisib, CDK4/6i, palbociclib|
|NCT02206984||ER+||Letrozole, anastrazole, fulvestrant||Lobular only|
|NCT02971748||ER+, inflammatory||Endocrine, various
|pembrolizumab||If no pCR after NAC|
|NCT02957968||ER+, TNBC||“Epigenetic” drug decitabine||pembrolizumab||various|
|NCT02282345||TNBC||PARPi talazoparib||BRCA+ only|
|NCT03045393||TNBC||Mirvetuximab Soravtansine||If no pCR after NAC|
|NCT02689427||TNBC AR+||Enzalutamice (androgen suppressor)||paclitaxel|
|TNBC, inflammatory||panitumumab||CT, AC||randomized|
|NCT02326974||HER2+||Anti-HER2 T-DM1 and pertuzumab|
|NCT02605915||HER2+||Anti-HER2 trastuzumab, T-DM1||atezolizumab||Docetaxel or AC||randomized|
|NCT02689921||HER2+, ER+||aromatase inhibitors||Anti-HER2 Trastuzumab, pertuzumab|
|NCT02907918||HER2+, ER+||letrozole||Anti-HER2 trastuzumab CDK4/6i, palbociclib|
Some of these new neoadjuvant treatments may turn out to be not only more effective, but better-tolerated as well (fewer side effects). Enrollment of newly diagnosed breast cancer patients is of critical importance for developing these new approaches.