Advances in the treatment of advanced estrogen receptor positive breast cancer

estrogen receptor positive breast cancer

Luminal estrogen receptor positive HER-2 negative breast cancer is the common type of breast cancer, accounting for 70%  of all breast cancer. Endocrine therapy of estrogen receptor positive HER2 negative advanced breast cancer is very effective, however, many patients will have disease recurrence as a result of endocrine therapy emerging resistance. In this post, I will review our recent understanding of resistance mechanisms how this understanding translating into new therapies.

Resistance mechanisms: while upregulation of receptor tyrosine kinase signaling is seen as common mechanism for endocrine resistance, there are several inter-related other mechanisms are in play in the background,

  • Mutations in the gene encoding for estrogen receptor (ESR1).
  • Activation of the mTOR pathway.
  • Cyclin dependent kinase 4 (CDK4) and (CDK6) proliferation.
  • Mutations in the PIK3CA pathway
  • Others

While the standard of care for treating Estrogen Receptor positive advanced breast cancer was essentially Tamoxifen for premenopausal patients, and an aromatase inhibitor (AI)for postmenopausal patients. The earlier change to such approach was the use of selective estrogen receptors down-regulators (SERDs) such as fulvestrant in treatment naive advanced ER-positive advanced breast cancer as evidenced to be superior to AI from the FALCON trial.

Several completed trials changed the landscape of treating Advance ER-positive breast cancer

Inhibition of CDK4 and CDK6: several trials looked into the efficacy of CDK4 and CDK6 inhibitors, some are completed and published, some are still ongoing or starting. The three clinical settings were CDK4 and CDK6 were studies can be summarized as follow,

A. Endocrine naive advanced ER-positive HER2 negative breast cancer. Trials can be summarized in the following table

TrialTreatmentResult
PALOMA-1
Phase 2
Letrozole with or without
Palbociclib
PFS: 20 months vs 10 months statistically signficant (SS) favoring Palbociclib containing arm
PALOMA-2
Phase 3
Letrozole with or without
Palbociclib
PFS: 24 months vs 14 months (SS), favoring Palbociclib containing arm.
MONALEESA2
Phase 3
Letrozole with or without
Ribociclib
PFS: not reached vs 15 months (SS) favoring Ribociclib containing arm

Based on the above the addition of a CDK4 and CDK6 inhibitor to AI became the standard of care in the treatment of patients who are ER-positive HER2 negative presenting with advanced breast cancer.

B. Endocrine resistant advanced ER-positive HER2 negative breast cancer. Trials can be summarized in the following table

TrialTreatmentResult
PALOMA-3
Phase 3
Fulvestrant with or without
Palbociclib
Positive for the palbociclib arm
MONARCH-1
Phase 2
Fulvestrant with or without
Abemaciclib
Early reports favoring Abemaciclib arm
MONARCH-2
Phase 3
Fulvestrant with or without
Abemaciclib
Early reports favoring
Abemaciclib arm

Abemaciclib is undergoing review for FDA approval (7/2017)

C. In the adjuvant setting in high risk ER-positive HER2 tumors. Trials are on going and continue to accrue.

  • EarLee-1 trial examining ribociclib plus adjuvant endocrine therapy.
  • NSABP B-58 examining abemaciclib plus adjuvant endocrine therapy.

The use of CDK4 CK6 inhibitors safety profile is acceptable, with asymptomatic neutropenia being the most common side effect with palbociclib and ribociclib. On the other hand, abemaciclib causes less neutropenia but more diarrhea and fatigue.

mTOR inhibition:  several mTOR inhibitors are undergoing clinical trials. One published trial the BOLERO-2 trial should efficacy of everolimus combined with exemestane in ER-positive HER2 negative endocrine resistant tumors which led to it’s FDA approval for such indication, however, the use of everolimus is associated with toxicities that require close monitoring and early management such as mucositis, skin rash,  non-infectious pneumonitis, fatigue, and pneumonia.

PI3K inhibition: multiple ongoing trials are ongoing at the moment to look into PI3K inhibitors. Of note, however, is the SOLAR-1 trial which is looking into utilizing aleplisib in a specific patient population with  PIK3CA mutant status.

Future direction: While our understanding of resistance mechanisms in ER-positive HER2 negative advanced breast cancer has paved the way to the above cited new interventions that is now the standard of care there are still major hurdles,

  • What are the predictors of optimal response to each one of them? is there one better than the other?
  • Which group of patients can be treated with Endocrine therapy alone? and be saved additional toxicity?
  • Can we have exact genomic targeted therapy for a specific mutation?

Research is ongoing to answer such questions.

 

 

 

In preparation for this post, I reviewed this lancet publication, which can be accessed by here.

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