Oncology

BREAST CANCER

The expression of estrogen or progesterone receptors drives cancer promotion in breast tissue.  67% of breast tumors are hormone receptor positive.  The presence of the estrogen (ER) or progesterone (PR) receptor is clinically important and depends on pathologic evaluation. The various combinations include ER⁺, PR⁺, and ER⁺/PR⁺.  Only hormone positive tumors will respond to the drugs discussed below.  The major drug classes include: selective estrogen receptor modulators (SERMs), ER down-regulators, aromatase inhibitors, and LHRH agonists. The two main therapeutic approaches that are used for breast cancer treatment are to:

1) block the effects of estrogen by targeting the ER which can be accomplished by SERMs and ER down-regulators.

2) inhibit the amount of ligand produced by reducing the production of estrogen which is accomplished with aromatase inhibitors and GnRH (LHRH) receptor agonists.     

Selective estrogen receptor modulators (SERMs)  

The archetypal SERM is tamoxifen. SERM drugs competitively inhibit estrogen (estradiol) from binding to the estrogen receptor (ER) and reduce the growth-promoting effects of estrogen. Since they have mixed actions as both agonists and antagonists, they are called modulators. There are two subtypes of estrogen receptors (ERα and ERβ). SERM drugs function either as agonists or antagonists, depending on the tissue. In the breast tissue (and brain) they act as antagonists, whereas in bone, endometrium, and the cardiovascular system they act as agonists. Because the breast endometrium contains both receptor subtypes, so you can see mixed actions in this tissue. The selectivity for the various receptor subtypes increases the therapeutic index of the drug. The estrogen receptor dimerizes when engaged by agonist ligands, and this facilitates interaction with estrogen response elements (ERE’s) within the promoter regions of estrogen-driven genes. Upon binding, the genes become activated and proteins that drive growth and proliferation are produced. In terms of the mechanism of action, SERMs block this activity in breast tissue and can promote it in uterine (endometrial) tissue, thus women on long term treatment should be monitored for uterine bleeding. Improvements in the chemistry of other members in this drug class, has produced drugs specific for various diseases. For example, raloxifene has profound effects on bone and is approved for osteoporosis. It has minimal cardiac effects and some ischemic effects (higher risk of thrombotic events).  Most SERMs in post-menopausal women produce vulvo-vaginal atrophy which can be treated with ospemifene which has agonist effects on vaginal epithelium.   

Tamoxifen can be used in both premenopausal and postmenopausal women for both the treatment and prevention of breast cancer since the drug targets the receptor. This drug is orally administered and undergoes dramatic hepatic biotransformation and is ultimately secreted in the stools.  Several CYP enzymes are responsible for the biotransformation of this drug (CYP2D6, etc.) and polymorphisms account for poorer outcomes. The major metabolite with the most activity is endoxifen. Tamoxifen will also slow the development of osteoporosis and lower serum LDL levels, which is cardioprotective. Typical side effects for tamoxifen include hot flashes, vaginal atrophy, nausea/vomiting, hair loss, vision problems, and rashes.  Weight gain, vaginal bleeding, and hot flashes are also reported. Major adverse effects include an increased risk (2-3x) for endometrial cancer and thromboembolic events. There is tamoxifen resistance as well. Innate resistance occurs through genetic variantions in CYP2D6 which have been reported in several ethnic populations. Acquired resistance can be observed in the cross-talk signaling of the Her2v mutated tyrosine kinase and the estrogen receptor. While tamoxifen can be used both as a treatment and for breast cancer prevention, raloxifene is used for the prevention of breast cancer in high-risk women (as well as the prevention of osteoporosis).  Raloxifene would be contraindicated, however, in a patient with a history of DVT/PE (deep vein thrombosis/pulmonary embolism).   

ER down-regulators

Fulvestrant is a selective estrogen receptor down-regulator (SERD). It behaves as a competitive ER antagonist with no agonist activity, and it promotes proteasomal degradation of ERα protein (hence 'down-regulator'). This is a unique attribute for an antagonist (remember the beta receptor blockers tend to increase the beta 1 expression over time). This drug has a higher affinity for the ER than tamoxifen (100 x greater) and can dramatically reduce tumor growth and proliferation through reduced ER-mediated signaling. Fulvestrant is administered monthly, via intramuscular injection for the control of post-menopausal breast cancer management with metastasis (usually after tamoxifen). It is not indicated for patients who are pregnant or may be breast-feeding. Side effects include injection site pain, hot flashes, headache, muscle ache, and bone pain. Angioedema and urticaria are possible. Elevated liver function tests can occur.      

Aromatase inhibitors 

Aromatase (the cytochrome P450 enzyme CYP19A1) converts androstenedione to estrone, and testosterone to estradiol which can occur in both the ovary and in adipose tissue.

Anastrozole is a third generation, non-steroidal imidazole which binds to CYP19.  Dose-dependent reductions in androgen aromatization are observed.  This drug is hepatically metabolized and excreted through the biliary system. Anastrozole is used as an adjuvant therapy in post-menopausal women with early-breast cancer and as an first-line therapy for advanced breast cancer. Anastrozole has similar side effects as tamoxifen, but with reduced frequency and severity. It does however cause more musco-skeletal effects and a greater reduction in bone-mineral density compared to tamoxofen.  This side effect can be managed by co-administration of bisphosphonates.   

Letrozole has similar chemical structure as anastrozole, and the same MOA. It reduces the aromatization of hormones by up to 99%, and reduces the expression of cancer biomarkers (HER1 and HER2v). Like anastrozole, it is approved as first-line adjuvant hormonal therapy in postmenopausal women with early-stage breast cancer and as treatment for advanced breast cancer. Letrozole side effects also include hot flashes and night sweats, nausea/vomiting, hair thinning, (but fewer incidences of cardiovascular side effects), elevated cholesterol, reduced libido, increased risk of fractures (which can be prevented by the co-administration of bisphosphonates to reduce the number of fractures).  

Exemestane is another aromatase inhibitor, but with a steroid-based chemical structure, that binds covalently to the CYP19 enzyme and irreversibly inactivates it. It is sometimes called a suicide inhibitor. This drug is indicated for women who have completed 2-3 years of adjuvant tamoxifen therapy.   

GnRH (LHRH) receptor agonists

GnRH (gonadotropin releasing hormone, a.k.a. luteinizing hormone-releasing hormone, or LHRH) receptor agonists, are synthetic analogues of the endogenous peptide hormone GnRH. The most prescribed drugs in this class are are goserelin and leuprolide. Administration of GnRH agonists causes gonadal suppression, due to triggering of a negative feedback loop in the hypothalamic-pituitary-gonadal axis (further details are included below for prostate cancer, since these drugs are also used for prostate cancer).  The synthetic drugs are longer lasting and more potent than endogenous GnRH, and are indicated for premenopausal patients only.  Typical side effects include nausea/vomiting, hot flashes, depression, tumor flare (transient) and QT interval prolongation.   

There are different treatment strategies for breast cancer depending on whether or not the patient is pre- or post-menopausal.  Premenopausal breast cancer patients can be treated with tamoxifen and GnRH agonists.  Aromatase inhibitors will not work in these patients since they have functional ovaries and the drugs cannot overcome the estrogen production from the ovary. In contrast, post-menopausal patients with breast cancer can be treated with either of the following: aromatase inhibitors, tamoxifen, or fulvestrant. GnRH receptor agonists are ineffective in post-menopausal these patients since the ovary/hypothalamic axis is non-responsive due to menopause.    

PROSTATE CANCER

Prostate tumors are also driven by hormone activity. Several drug classes are used to target prostate cell growth: GnRH receptor agonists and antagonists, anti-androgens and enzyme inhibitors.   

GnRH receptor agonists are used in both pre-menopausal women with breast cancer and in men with prostate cancer.  Goserelin and leuprolide were covered above. Triptorelin and histrelin are also used in prostate cancer therapy. In men, the use of these drugs results in chemical castration. Testosterone levels will fall, testes will remain, but will shrink in size. Histrelin is not indicated for breast cancer treatment, but is indicated for the treatment of uterine fibroids. These drugs are peptides and must be injected. All GnRH receptor agonists target the receptors that are expressed in the pituitary gland, with receptor activation causing a dramatic surge of LH which stimulates the testes. This in turn causes a surge of testosterone to stimulate the prostate, causing a brief expansion of cancer activity at the prostate (tumor flare). However, the overstimulation of the pituitary switches on a feedback loop to reduce the number of GnRH receptors, which in turn causes a rapid reduction in production of LH and FSH that is accompanied by a fall in testosterone levels. The same would hold true for breast cancer, except via estrogen's effects on the ovaries. These drugs have clinical indications outside of prostate and breast cancer, including male and female infertility (short-term), diagnosis of delayed puberty, ovarian overstimulation, endometriosis, leiomyomas, etc.  For prostate cancer, these drugs have a major role in metastatic disease. They can also be used in combination with local therapy for early disease in patients with increased risk for cancer recurrence. The tumor flare mentioned earlier manifests clinically as bone pain, urinary symptoms, bladder obstruction, and neuropathy. These are the direct testosterone-stimulating effects on various tissues and can be alleviated with anti-testosterone (anti-androgen such as bicalutamide) therapy in combination with GnRH receptor drugs early in the treatment phase.      

GnRH receptor antagonist

Degarelix offers the same anti-androgen effects that GnRH receptor agonists provide, but without the corresponding tumor flare just described. The target is still the pituitary GnRH receptors, but the drug competes with endogenous GnRH for receptor binding and effectively blocks receptor activation, which in turn eliminates the secretion of LH by the testes, and this ultimately disrupts the secretion of testosterone. Degarelix is also FDA-approved for the treatment of advanced or metastatic prostate cancer. Common adverse effects including hot flashes, fatigue, weight gain, increased liver enzymes, and injection site pain are reported.   

At some point, prostate tumors are likely to acquire resistance to the above androgen-deprivation therapy (ADT). This is due to the fact that as tumor cells grow and metastasize, they are able to make their own androgens outside of the testes. Remember, progesterone-derivatives can be converted to testosterone which is where another class of drugs becomes useful, the enzyme inhibitors. 

Enzyme inhibitors 

Abiraterone is an enzyme inhibitor of CYP17 (17-α-hydroxylase; CYP17A1) which converts 17-hydroxyprogesterone to androstenedione, the precursor to testosterone. This is used for metastatic, castration-resistant prostate cancer to treat extra-testicular sources of testosterone. It is often given in combination with the corticosteroid.prednisone and can cause fluid retention, hypertension, hypokalemia, adrenal insufficiency, hepatotoxicity, diarrhea, hot flashes, and fatigue.  

Androgen receptor antagonists

These drugs are competitive antagonists of testosterone at the androgen receptor (AR). Therefore, any testosterone (from testes or otherwise) will have to compete with these high-affinity drugs to bind to the receptor.  Flutamide is the principal drug is this class drug (also nilutamide and bicalutamide are available) and will prevent both testosterone and dihydrotestosterone (DHT) from binding to the AR on prostate cancer cells. Typical side effects are characteristic of testosterone-blockade: gynecomastia, less muscle mass, feminization, erectile dysfunction, GI changes, and depression. Enzalutamide also belongs to this class of drugs.  

In summary, the initial treatment of metastatic prostate cancer can include the following regimens: 

• GnRH receptor agonist + antiandrogen (short-term, for tumor flare)  

• GnRH receptor agonist + antiandrogen = CAB (combined androgen blockade)  

• GnRH receptor antagonist (degarelix) 

Michael Bradaric (Rush Medical College)

HER2 (encoded by the ERBB2 gene) is a tyrosine kinase that is one of the receptors for EGF (epidermal growth factor). HER2 is often mutated in tumors (approximately one quarter of breast cancers, for example), and mutant HER2's dysregulated activity drives several pathways that promote cancer cell phenotypes. Among the most studied downstream pathways that are activated by EGF are the MAPK and PI3K/Akt pathways. Mutations in the HER2 protein (referred to has HER2v here) are associated with poor prognosis. There are essentially two approaches for targeting HER2v positive cancers

• monoclonal antibodies to inhibit receptor activation
• small-molecule inhibitors to block tyrosine kinase activity

 Both of these drug categories results in a loss of activity of the tyrosine kinase and an inhibition of the oncogenic potential of EGF pathway activation. Additionally, monoclonal antibodies can elicit immunological anticancer effects, including antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cell-mediated phagocytosis (ADCP), and complement mediated cytotoxicity (CDC). 

Monoclonal antibodies:

Trastuzumab (Herceptin ®) binds directly to HER2 and induces antibody-dependent cell mediated cytotoxicity (ADCC). These agents are large protein molecules that share common IgG domains. Trastuzumab has become the standard of care for HER2v positive breast tumors with lymph node involvement. It is also approved for a subset of HER2v+ gastric tumors and can be combined with classic chemotherapeutic agents.  Because it is a large IgG macromolecule, monoclonal drugs are administered via infusion and infusion-type reactions are common. Trastuzumab is teratogenic and cannot be administered to pregnant women. It also has a black box warning for heart conditions (which can be magnified if given with anthracycline chemotherapy). Therefore, patients with reduced cardiac function or heart failure (low ejection fraction less than 35%) may not be able to tolerate trastuzumab.  Fatigue, nauses/vomiting, and headache are common side effects.  Low white blood cell counts and lung manifestations can occur since there are tyrosine kinase receptors in the lung.

Pertuzumab is a second-generation anti-HER2 drug, but it interacts with a different binding site (epitope) on HER2. It is indicated for early and metastatic breast cancer and is often combined with other chemotherapeutic agents. It is embryo-lethal and cardiotoxic and can precipitate heart failure as demonstrated by a reduced ejection fraction.

Some of the monoclonal antibodies can be conjugated to chemotherapeutic drugs (antibody-drug conjugates, or ADCs), which allows the targeted delivery of cytotoxic agents to HER2v positive cells. The cytotoxic payloads are only released once they have been internalized by the target cells, with the aim of reducing bystander killing. Two trastuzumab ADCs that are in clinical use are  trastuzumab emtansine, a.k.a. ado-trastuzumab (FDA approved in 2013), and trastuzumab deruxtecan (FDA approved in 2019). Emtansine is a β-tubulin blocker, and deruxtecan is a topoisomerase I inhibitor.

N.B. Pre-2022 the INNs for monoclonal antibodies all contained the -mab suffix (or 'stem'). However, in mid 2022, the nomenclature for monoclonal antibodies was update by the WHO, to better delineate the emerging lineages of monoclonals and their derivatives. '-mab' was discontinued, and has been replaced by four new stems -tug, -bart, --ment and -mig. See Koch et al. (2022) International nonproprietary names for monoclonal antibodies: an evolving nomenclature system for a full description of these changes doi: 10.1080/19420862.2022.2075078.

Tyrosine kinase inhibitors:

A range of small molecular weight kinase inhibitors are used in the treatment of HER2v positive cancers. Due to similarities in the structure of the drug-binding sites within the tyrosine kinases, most of theses drugs inhibit several related growth factor RTKs, in addition to the EGF receptors, including PDGFR, KIT, FLT3 and CSF1R, and so are generally viewed as 'multi kinase' inhibitors. However, their polypharmacology undoubtedly contributes to their clinical efficacy. Over the years many inhibitors with anti-angiogenic and anti-prolifertive activities have been developed and brought to the clinic, and third generation inhibitors that selectively and irreversibly target mutated versions of EGFRs (whilst sparing wild type receptors) are available.

Lapatinib is a dual tyrosine kinase inhibitor which interrupts the HER2v and epidermal growth factor receptor (EGFR) pathways. It is used in combination with other chemoterapeutics in advanced or metastatic breast cancer cases. Due to its small molecular weight the drug is capable to penetrate the blood-brain barrier and therefore can be used in the management of brain metastatsis.

Tucatinib is a selective HER2v inhibitor, it is currently used for advanced unresectable or metastatic HER2-positive breast cancer, including those with brain metastases, who have received one or more prior anti-HER2-based regimens in the metastatic setting.

Examples for other multi-tyrosine kinase inhibitors include those below. However, these drugs are rarely used in breast cancer.

sunitinib- targets VEGFR2, PDGFR, Kit, FGFR, and others - first approved in 2006

pazopanib - targets VEGFR1, VEGFR2, VEGFR3, PDGFRβ, FGFR1, Kit and CSF1R- first approved in 2009

cabozantinib- targets VEGFR2, MET, RET- first approved in 2012

regorafenib- targets VEGFR2, BRAF- first approved in 2012

axitinib-  targets VEGFR1, VEGFR2, VEGFR3, PDGFR, Kit- first approved in

nintedanib- targets VEGFRs, PDGFR and FGFR- first approved in 2014

osimertinib - an irreversible EGFR inhibitor, with selectivity for receptors with mutations that either sensitize the receptor, or cause drug resistance (e.g., the T790M mutation). The compound is less effective against the wild-type receptor- first approved in 2015

olmutinib- an irreversible inhibitor that targets mutant EGFR selectively over wild-type- approved in South Korea in 2016

Michael Bradaric (Rush Medical College)