How Do Cancer Cells Develop Treatment Resistance? Hormonal Treatment Resistance in Breast Cancer

Breast cancer’s dependence on the female hormone estrogen has long been known. First, in 1896 , the respected medical journal Lancetpresented ovary removal as a “new treatment for inoperable breast cancer”; medicines have now replaced this method.

Before menopause, ovaries produce estrogen; afterward, sources include fat tissue and adrenal glands. Methods for suppressing female hormones include:

• Ablative Methods
  • Ovary removal
  • Adrenal gland removal
• Methods Suppressing Hormone Production (Synthesis)
  • Aromatase inhibitors
  • GNRH antagonists
• Drugs Developed Against the Estrogen Receptor
  • Selective estrogen receptor modulators (tamoxifen),
  • Selective estrogen receptor inhibitors (fulvestrant)

Trials show these options are effective in hormone receptor-bearing breast cancer, both as postoperative preventive treatment and in disseminated disease.

Despite Standard Treatment, Early-Stage Breast Cancer Can Recur in %20 of Patients

We know hormonal therapy produces responses in %65-70 of disseminated disease patients. This raises the question, “Do some patients develop hormonal treatment resistance over time, or do some have resistance from the outset?” as an issue.

Resistance to Hormonal Treatment

Primary Resistance (Existing Initially)

• Recurrence during the first 2 years of hormonal adjuvant treatment
• Progression during the first 6 months of hormonal treatment in disseminated disease

Secondary Resistance (Acquired Later)

• Recurrence after the first 2 years of hormonal adjuvant treatment or after treatment completion
• In disseminated disease, initial benefit followed by progression after 6 months of hormonal treatment

Mechanisms of Resistance:

1. Estrogen Receptor Mutation

Estrogen binds its nuclear receptor (ER = estrogen receptor), stimulating nuclear growth signals while interacting with other receptors to activate intracellular growth and proliferation. There are two ER types: ER1 and ER2. Mutation in active ER1 prevents transmission of hormonal suppression responses and activates other growth hormone pathways.

Although this resistance-causing receptor mutation was discovered in 1990, its treatment relevance was overlooked until recent years. It occurs in %11-55 of recurrent or disseminated disease. Studies show patients with this mutation respond less to tamoxifen or fulvestrant

2. HER2 Gene Overexpression

Human growth epithelial factor (HER), a cell-surface receptor, transmits growth and proliferation signals. Studies show reciprocal communication with estrogen receptors. In %10 of hormone receptor-bearing breast cancers, HER2 is overexpressed. Her2 inhibitors (trastuzumab) are standard in these patients.

3. HER2 Gene Mutation

Unlike HER2 overexpression, this involves a genetic change in the receptor’s intracellular signaling region, producing continuous growth signals without external stimulation. It occurs in %2 of breast cancers and up to %20 of invasive lobular cancers. Neratinib has shown clinical efficacy in this mutation, and a trial combining fulvestrant and neratinib continues.

4. Fibroblast Growth Factor Receptor (FGFR)

With four receptor types involved in cell growth, proliferation and differentiation, overexpression occurs in %16-27 of hormone receptor-bearing breast cancers. Drugs have been developed against it. Dovitinib showed phaseII activity, and trials with hormone-suppressing drugs continue.

5. Phosphatidylinositol 3 Phosphate (PI3P)

Intracellular phosphatidylinositol 3 kinase transmits external stimuli and forms the central hub of the Akt/mTOR pathway activated by these stimuli. In %30-40 of hormone receptor-bearing patients, its coding gene may mutate. PI3P alteration is the most common genetic change in hormonal resistance. Trials show mTOR inhibitors are effective when this mutation exists.

The mTOR inhibitor Everolimus received FDA approval for aromatase-inhibitor-resistant breast cancer. New drugs directly blocking PI3K are being developed, but frequent serious adverse effects complicate use and limit efficacy. Common problems include diarrhea, rash and elevated liver enzymes. I believe management will improve as more genetically specific drugs develop.

6. Cyclin D, CDK4\6 Inhibitors

Cells pass through stages when proliferating. CDK4\6 proteins control resting and synthesis phases, and changes in them contribute to resistance. Palbociclib (Ibrance), an inhibitor, prevented growth of hormone receptor-bearing breast cancer cells in laboratory studies. Following a trial with letrozole, it received FDA approval and entered first-line use in America for disseminated stage 4 hormone receptor-positive breast cancer.

7. Histone Deacetylase (HDAC) Inhibitors

HDAC is a protein with enzymatic activity. Its inhibition stops proliferation and directs cancer cells toward death. Entinostat inhibited signaling pathways involved in aromatase inhibitor resistance in laboratory studies. Subsequent phase II trials combining it with exemestane (a postmenopausal aromatase inhibitor) extended both time to progression and overall survival. Trials continue.

Promising Targeted Drugs Developed for Hormone Receptor-Bearing Breast Cancer

Drug: Everolimus

Mechanism: mTOR inhibitor

Current Status: FDA-approved with exemestane as second-line treatment for hormone receptor-bearing metastatic breast cancer

Adverse Effects: Fatigue, stomatitis, high blood sugar, pneumonitis

Drug: Palbociclib, Ribociclib, Abemaciclib

Mechanism: CDK4/6 inhibitor

Current Status: Palbociclib is FDA-approved for hormone receptor-bearing metastatic breast cancer. Trials of all three agents continue in adjuvant, preoperative and metastatic settings.

Adverse Effects: Neutropenia (without febrile neutropenia), ECG changes, fatigue, diarrhea

Drug: Alpelisib, Taselisib, Buparlisib, Pictilisib

Mechanism: PI3K inhibitor

Current Status: Clinical trials continue

Adverse Effects: High blood sugar, rash, liver toxicity

Drug: Entinostat

Mechanism: HDAC inhibitor

Current Status: Given FDA breakthrough drug status. PhaseIII trial with Exemestane continues.

Adverse Effects: Fatigue, bone marrow suppression, diarrhea, nausea, vomiting

Drug: Dovitinib, Lucitinib

Mechanism: FGFR inhibitor

Current Status: Efficacy demonstrated preclinically; studies continue

Adverse Effects: Diarrhea, nausea, hypertension, liver toxicity, protein leakage into urine