On February 19, 2016, Pfizer’s Ibrance capsules (Palbociclib) received an approval from FDA, in combination with Letrozole, for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor-2 (HER2) negative advanced or metastatic breast cancer with disease progression followed by endocrine therapy.

Last year, FDA, approved PALBOCICLIB in combination with LETROZOLE (an aromatase inhibitor, for hormone dependent breast cancer in postmenopausal women), for the treatment of advanced stage breast cancer {estrogen receptor (ER) positive and human epidermal receptor -2 (HER 2) negative} in postmenopausal women.

Initially, both of these drugs were either used as single therapy (Letrozole alone) or in combination with other drugs (Palbociclib in combination with fulvestrant) for the treatment of hormone dependent breast cancer.

Types Of Breast Cancer

Breast cancers are categorized as follows by American Society of Cancer (ASC)

  • Estrogen Receptor (ER) or Progesterone Receptor (PR) Positive

It is an estrogen or progesterone dependent or hormone dependent cancer. This means that breast cancer cells have either excessive estrogen receptors or progesterone receptors or in some cases both receptors inside the cancer cells that bind to these endogenous hormones in the body and start proliferating uncontrollably and spread (metastases) to other parts of the body. This type of cancer is treated with hormone therapy (also called endocrine therapy).

The hormone therapy either blocks the receptors or lowers the levels of these hormones in the body. The aim is to either halt the binding of the receptor to the hormone or to keep the hormone levels low, either way the cells have minimum access to the hormone, essential for their growth or multiplication. This type of cancer is more prevalent in post-menopausal women. The aromatase inhibitors Anastrozole and Letrozole are now the first line treatment in women with advanced breast cancer whose tumors are hormone-receptor positive.

  • Estrogen Receptor (ER) or Progesterone Receptor (PR) Negative

This means that in such type of cancer, estrogen receptors or progesterone receptors are not present, in other words absent. Such types of cancers do not respond to hormone therapy and are aggressive or invasive in nature that tends to grow more quickly than hormone receptor-positive cancers. This type of cancer is treated with chemotherapy.

If relapse occurs, it is usually in the first few years after the treatment. This type of cancer is more common in women who have not yet gone through menopause.

  • Human Epidermal Receptor 2 (HER2)/ neu Positive

A type of breast cancer in which breast cancer cells have excessive HER2 neu receptors on the surface of the breast cancer cell or have extra copies of HER2 gene. The gene for HER2 neu protein in breast cancer cells instructs the cells to make the HER2 protein (a growth promoting protein). As a result, breast cancer cells have excessive amount of this HER2 protein which then binds to the HER2 receptors on the breast cancer cells and are termed as HER2/neu positive. These Cancers are treated with drugs that target HER2 protein.

The most common drug is Herceptin (Trastuzumab) and Lapatinib (Tykerb). Herceptin can be used either alone or in combination with cytotoxic chemotherapy.

  • Human Epidermal Receptor 2 (HER2)/neu Negative

Such cancers do not have excessive HER2 receptors, HER2 protein or extra copies of HER2 genes and do not respond to therapy for HER2 positive cancers. If HER2 negative cancer is hormone receptor positive, it will either benefit from hormone therapy, but may also include chemotherapy and/or targeted therapy

The standard initial treatment for HER2-negative metastatic breast cancer–is also hormone receptor positive–is the hormonal therapy (Tamoxifen, Fulvestrant, Letrozole, Anastrozole). However, chemotherapy may also be given but there is no specific type of chemotherapy recommended for this type of breast cancer.

The American Society of Cancer recommends following chemotherapeutic drugs;

Many drugs are available, including types of drugs called Taxanes and Anthracyclines. In addition, platinum-based drugs, as well as the drugs Capecitabine (Xeloda), Eribulin (Halaven), Gemcitabine (Gemzar), Ixabepilone (Ixempra), and Vinorelbine (Navelbine) may be used.

  • Triple-negative

This type of breast cancer has neither estrogen or progesterone receptors nor do they have enough HER2 proteins, they are called triple-negative. This type of cancer is frequent in young females and females of African-American or Hispanic/Latina origin. Triple negative cancers are the most aggressive and difficult to treat, since, all drug therapies are either aimed at hormone receptors or at HER2 protein or receptors. Triple-negative breast cancers are metastatic in nature, i.e. they tend to grow and spread more quickly than most other types of breast cancer. This type of cancer is mostly treated with chemotherapy.

Since, the tumor cells don’t have hormone receptors so the hormone therapy is not helpful in treating these cancers, plus they don’t have too much HER2, so drugs that target HER2 aren’t helpful either.

  • Triple-positive

This term refers to the presence of both ER-positive and PR-positive receptors and also have too much HER2 in addition. These cancers can be treated with hormone drugs as well as drugs that target HER2.

Significance Of Ibrance Approval By FDA

Palbociclib (PD-0332991) is a cyclin- dependent kinase (CDK) inhibitor (it interacts with a cyclin-CDK complex to block kinase activity). Cyclin-dependent kinases (CDKs) are protein kinases (special proteins) that are involved in regulation of cell cycle.

CDKs are considered a potential target for anti-cancer medication (the drug Palbociclib, selectively interferes with the action of these specific protein kinases, the process of cell cycle regulation is interrupted and the cell dies). Palbociclib possess a high level of selectivity for CDK4 and CDK6 over other cyclin-dependent kinases.

Preclinical evidence suggests that Palbociclib possesses growth-inhibitory activity in ER positive breast cancer cells and can effectively synergize with anti-estrogens drugs (Tamoxifen, Raloxifene).

These anti-estrogen drugs or endocrine therapies are the main stay of treatment for these hormone receptor positive or hormone-dependent cancers. Although, the hormone therapy remarkably reduces the relapse rate after early-stage cancer is diagnosed, still many women undergo relapse during or after competing adjuvant therapy (supplemental chemotherapy that follows after surgery and radiation has been performed to attack micro metastasis).

Relapse of the cancer is a critical challenge since the patient has already endured the disease and the severe side effects of anti-cancer drugs. Monotherapy with an aromatase inhibitor or Tamoxifen has shown limited clinical benefit. Fulvestrant, a selective estrogen-receptor degrader also possesses only modest activity in this population of patients, so development of effective therapies, which can reverse resistance to endocrine therapy, is an utmost necessity.

Superiority Of Newly-Approved Drugs

  • The newly-approved combination of Palbociclib with Letrozole has resulted in a median progression –free survival (relapse free period) of 20·2 months as compared to median progression-free survival of 10.2 months for the Letrozole group only, in the open-label, randomized phase 2 study.

This progression-free survival period of 20.2 months with Palbociclib and Letrozole combination was also superior to the median progression-free survival period of 9.2 months with Palbociclib and Fulvestrant combination and 3.8 months with placebo–fulvestrant.

The investigators, therefore, concluded that the addition of Palbociclib to Letrozole in this phase 2 study significantly improved progression-free survival in women with advanced estrogen receptor-positive and HER2-negative breast cancer and a phase 3 trial is currently underway.