First of all, before starting the formal review, please read the following questions, and after our article, you can come back to see if your knowledge of these questions has been updated.
1. Which patients need to receive endocrine therapy?
2.What is the order of endocrine therapy?
3.Can endocrine therapy be combined with other medications? How to combine them?
The first question is: Which drugs should be used as first-line treatment for advanced hormone receptor-positive breast cancer patients? When to use hormone and when to use chemotherapy?
For each patient, we need to do a comprehensive assessment: hormone receptor, Her2 status, the location of metastases and the presence of symptoms, what kind of treatment the patient has received in the past, and how long the discontinuation period is. In general, the first line of treatment is endocrine therapy in the absence of life-threatening conditions, and chemotherapy in the presence of life-threatening conditions. This “life-threatening” condition is defined as severe internal organ failure, including jaundice, crisis laboratory results, and rapid disease progression. It is important to note that during the first few months of endocrine therapy, the tumor may not respond to endocrine therapy and the disease is often in a “stable” state, even though some tumor indicators may progress. In the long run, ER positive patients benefit from long-term survival despite the slow response to endocrine therapy.
The second question is: What is the order of endocrine therapy drugs?
In the field of endocrine therapy for advanced breast cancer, the concept of first-line, second-line, and third-line seems to be not so clear, and which endocrine therapy drugs to be used for patients depends on which drugs have been used for postoperative adjuvant therapy and under which circumstances the tumor progresses. The concept of “exposing patients to all available endocrine therapy drugs” is more in line with the concept of endocrine therapy for advanced breast cancer. What are the drugs available to us now? Tamoxifen, aromatase inhibitors (anastrozole, exemestane, letrozole), and fulvestrant, from which we can select drugs that the patient has not used before (or has relapsed more than 1 year after stopping). However, there are still several issues worth discussing regarding the order of medication administration.
A clinical phase 2 study called FIRST compared the effectiveness of fulvestrant and anastrozole in the first-line treatment of progressive breast cancer, and the results of this study were reported at the 2014 San Antonio Breast Cancer Conference. The study included a total of 205 endocrine-untreated patients randomized to either fulvestrant (500 mg, intramuscularly on days 0/14/28 of dosing) or anastrozole (1 mg, orally) and showed that patients on fulvestrant had a significantly longer time to disease progression (TTP) with the drug, and as the study progressed, the investigators changed the endpoint to a more convincing OS and the results were found: overall survival was 54.1 months in the fulvestrant group compared with 48.4 months in the anastrozole group, also significantly prolonged. However, it is worth noting that not all patients were involved in the OS follow-up, so we need to be cautious about concluding that OS was “significantly improved”. This study suggests that perhaps first-line use of fulvestrant, a complete ER antagonist, may be better than aromatase inhibitors (AI class). However, due to the differences between intramuscular and oral agents and the fact that this was a clinical phase 2 study, no conclusions can be fully drawn. A clinical phase 3 study called FALCON avoids this problem by using both injectable and oral “placebo drugs” and the results of this study will be published in 2016 (NCT01602380).
Third, how can endocrine therapy be combined with other drugs (e.g., CDK4/6 inhibitors, mTOR inhibitors, PI3K inhibitors, etc.)?
Drugs currently being studied in advanced breast cancer include the CDK4/6 inhibitor Palbociclib, PI3K inhibitors Buparlisib and Pictilisib.
When it comes to studies of the CDK4/6 inhibitor Palbociclib in combination with endocrine therapy, the PALOMA-1, PALOMA-2 and PALOMA-3 series of studies must be mentioned. Preclinical basic studies have found that the CDK4/6 signaling pathway is important in ER-positive tumors, suggesting that perhaps CDK4/6 in combination with endocrine therapy could be synergistic. the PALOMA-1 study is a clinical phase 2, open-label, multicenter study comparing letrozole in combination with or without the CDK4/6 inhibitor drug Palociclib in ER+/ Her2-progressive postmenopausal breast cancer patients in first-line treatment. The results showed more clearly that Palbociclib in combination with letrozole was able to extend PFS by 2-fold compared to letrozole alone, a truly surprising finding, in addition to CDK4/6 side effects within a predictable and manageable range. Based on the results of this study, the FDA will award Palbociclib as an accelerated development drug. Further clinical phase 3 studies related to PALOMA-1 are ongoing.
The next study, PALOMA-2, is similar to PALOMA-1, also in postmenopausal progressive ER+/Her2- patients, and also compares the ability to improve survival with the addition of Palbociclib to letrozole, except that the study is not open-label and adds placebo to the letrozole-alone arm, and the primary endpoint of the study is PFS. The results of this PALOMA-2 study showed an improvement in PFS from 9 months to 14 months with an HR of 0.5, which was also very good.
In addition to the PALOMA-1 and 2 studies, the results of the PALOMA-3 study were equally impressive and were published in the New England Journal of Medicine in 2015 (Turner NC, et al. N Eng J Med. 2015; 373:209-19). The study was a large clinical phase 3 study comparing the second-line treatment of complete estrogen receptor antagonist-fluvestrant in combination with or without palbociclib in patients with advanced HR+/Her2-advanced breast cancer (the study was not limited to postmenopausal patients), and included patients who had failed front-line endocrine therapy, with the fluvestrant monotherapy arm given 500 Fulvestrant alone was given 500 mg (intramuscularly every four weeks) and fulvestrant combined with Palbociclib 500 mg (intramuscularly every four weeks) combined with Palbociclib 125 mg (orally for three weeks with one week off) in the fulvestrant combined with Palbociclib group. The results of the study were surprising: fulvestrant combined with Palbociclib was able to extend PFS from 3.8 months to 9.2 months with an HR of 0.422. Therefore, this study was terminated early. The results of this study suggest that the use of fulvestrant in combination with Palbociclib does significantly prolong patient survival compared to fulvestrant alone after failure of first-line endocrine therapy.
In addition to CDK4/6 inhibitors, what is the progress of research on PI3K inhibitors in combination with endocrine therapy?PI3K signaling pathway is a very common abnormal signaling pathway in ER+ breast cancer patients, and drugs that block this signaling pathway are: Akt-targeted drugs, mTOR inhibitors, pan-PI3K inhibitors or PI3K α/β-subunit inhibitors. The current state of research on these drugs is that there are multiple drugs in multiple studies that are “competing”, so we will only briefly introduce representative drugs and studies.
Buparlisib is a pan-PI3K inhibitor, and the phase 3 BELLE-2 study compared the addition of Buparlisib to fulvestrant to improve patient survival. Notably, the study stratified patients according to their PIK3CA mutation status at the time of inclusion. The results showed that the addition of Buparlisib was able to improve PFS from 5 months to 6.9 months compared to fulvestrant alone. The results of this study were reported at the 2015 San Antonio Breast Cancer Conference (S6-01). However, the problem with pan-PI3K inhibitors is that there are more side effects that can affect patients’ quality of life, such as hyperglycemia that occurs in 25% of patients. In contrast, those PI3K inhibitors that target the alpha/beta subunits will perform better in terms of side effects.
To summarize, the progress of endocrine therapy combined with other drugs: right now, there is no clear guideline whether endocrine therapy-based combination should be recommended to patients, but some very promising drugs (Erverolimus and Palbociclib) are currently in development and may change the guidelines; finding the most suitable index to determine whether patients need combination therapy , is the direction of future research.
Now, let’s return to the three questions at the beginning of the article.
1, which patients need to receive endocrine therapy?
Answer: Most patients with ER+ breast cancer need to receive endocrine therapy first, unless they have severe internal organ involvement or acute illness.
2.What is the order of endocrine therapy?
Answer: There is no clear order of endocrine medication. It is a more important concept to let patients accept all current endocrine therapeutic drugs during their treatment.
3.Can endocrine therapy be combined with other drugs? How to combine them?
Answer: There is no clear guideline on how to combine drugs. For patients who have received multiple drugs, endocrine therapy combined with other drugs can be considered; among the available combination drugs, the more promising drugs are CDK4/6 inhibitors, while PI3K inhibitors have not shown impressive performance so far.