Unfortunately, most advanced, hormone receptor–positive
breast cancers that initially respond to antiestrogens and
aromatase inhibitors eventually progress because they have
become treatment resistant. A recent FDA decision is helping
to address this challenge by providing a way to prolong the
time before a cancer becomes resistant to treatment.
In March 2017, the FDA approved the molecularly targeted
therapeutic ribociclib (Kisqali) for use in combination
with an aromatase inhibitor for treating postmenopausal
women with hormone receptor–positive, HER2–negative,
advanced breast cancer.
Ribociclib works by blocking the function of two specific
proteins that play a role in driving cell multiplication—
cyclin-dependent kinase (CDK) 4 and CDK6 (see Figure
14). Its FDA approval was based on results from a phase
III clinical trial that showed that adding ribociclib to the
aromatase inhibitor letrozole significantly increased the
time to disease progression among postmenopausal women
newly diagnosed with advanced, hormone receptor–
positive, HER2–negative breast cancer (146). Longer
follow-up of these patients has recently shown that the
combination also improves overall survival (147).
Research has shown that other breast cancers are
characterized by the presence of elevated levels of the
protein HER2 and that signaling networks triggered
by HER2 stimulate the breast cancer cells to multiply
and survive. HER2-positive breast cancers tend to be
aggressive; the outcome for patients was typically very
poor until researchers harnessed the basic understanding
of the biology of these cancers to develop a number of
therapeutics that target HER2. Trastuzumab (Herceptin)
was the first of these molecularly targeted therapeutics to
be approved by the FDA in 1998.
One use for trastuzumab in the treatment of patients with
HER2-positive breast cancer is as an adjuvant treatment
for those with early-stage disease, meaning it is given after
Checking Cell Multiplication Figure 14
Cell multiplication is a cyclical process with numerous
checkpoints (traffic lights) at which it can be stopped,
temporarily or more permanently. The phases of the cycle
between the checkpoints have different names (G1, S, G2, and
M). Cyclin-dependent kinase (CDK) 4 and CDK6 are two proteins
that promote passage through the checkpoint between the
G1 and S phases of the cell cycle. Blocking these proteins can
prevent cell multiplication. There are two anticancer therapeutics
approved by the FDA that exert anticancer effects by targeting
CDK4 and CDK6, palbociclib (Ibrance) and ribociclib (Kisqali).
They were approved for treating certain patients with breast
cancer in February 2015 and March 2017, respectively.
Figure adapted from ( 25)
HER2-targeted therapeutics have
been approved by the FDA for treating
certain patients with breast cancer:
ado-trastuzumab emtansine (T-DM1;
Kadcyla), lapatinib (Tykerb), neratinib
(Nerlynx), pertuzumab (Perjeta),
and trastuzumab (Herceptin).
continued from p. 65