- Obesity reduces the efficiency of anti-VEGF therapy in breast cancer patients .
- The microenvironment surrounding the tumor has increased amount of adipose tissue and less oxygen supply.
- Obesity promotes resistance to the treatment by producing pro-angiogenic and inflammatory factors like FGF-2 and IL-6 .
Obesity and its related factors induce resistance to antiangiogenic therapy in breast cancer patients, finds a study conducted at Massachusetts General Hospital (MGH). The findings of the study are published in the journal Science Translational Medicine
. The scientists also indicate that by studying the resistance new therapeutic strategies can be devised to treat breast cancer.
According to Joao Incio, MD, PhD, of the Edwin L. Steele Laboratories for Tumor Biology in the MGH Department of Radiation Oncology, the clinical and preclinical results show that obesity promotes resistance to anti-vascular endothelial growth factor therapy in breast cancer patients by producing several pro-angiogenic and inflammatory factors. He also indicates that by targeting the resistance factors antiangiogenic therapy can be restored in breast cancer treatment.
‘Obesity promotes resistance to anti-VEGF therapy for breast cancer by producing pro-angiogenic and inflammatory factors.’
Initially FDA approved the anti-vascular endothelial growth factor (VEGF) drug bevacizumab but later due to its inefficiency the drug was disapproved. Various studies have shown that obesity reduces survival rate in colon cancer patients, particularly those who undergo antiangiogenic therapy. Its role in other cancers is not clear.
Diagnosis shows that about 70% of breast cancer patients are obese, breast tumors contain a significant amount of adipose tissues. Obesity is associated with increased levels of angiogenic and inflammatory factors which promotes resistance to anti-VEGF. The current study mainly focuses on how obesity promotes resistance to anti-VEGF therapy for breast cancer by producing these factors.
The scientists first analyzed data from clinical trials of 99 breast cancer patients who were treated initially with bevacizumab and then with chemotherapy. The results showed that only a small fraction of people were benefited with anti-VEGF treatment. The researchers found that individuals with BMI (Body Mass Index) measurement of 25 or more were classified obese had tumors 33% higher compared to individuals who had BMI below 25. Samples of tumors from patients with higher levels of body fat had less vascular supply that interfered with chemotherapy response.
Patients with increased BMI had high levels of interleukin 6 (IL-6), a pro-inflammatory molecule, and fibroblast growth factor 2 (FGF-2), a pro-angiogenic molecule. These factors were also expressed in the nearby adipose tissues.
Various experiments were conducted on two mouse models with breast cancer-one with of triple-negative cancer and the other with estrogen receptor (ER)-positive cancer. The results supported the clinical research findings.
- The area surrounding the tumors in obese mice had many adipocytes and the cells had reduced oxygen levels, this was associated with reduced response to anti-VEGF drug .
- In the ER-positive model adipocytes and certain immune cells within the tumor overexpressed several inflammatory and angiogenic molecules, including IL-6. The response to anti-VEGF therapy was increased by blocking IL-6 .
- In triple-negative cancer model, obese animals had increased levels of FGF-2 but not IL-6. After blocking FGF-2, the response to the treatment increased .
- In both the models, blockade of either molecule did not improve treatment response in lean animals
"This is the first study to propose that markers such as body mass index could help personalize anti-VEGF therapy, with blockade of molecules like IL-6 or FGF-2 for overweight or obese cancer patients," says Incio. "Identifying and validating predictive biomarkers of treatment response and gaining the ability to classify patients regarding which of the more than a dozen currently available antiangiogenic therapies would be most beneficial remain major priorities in oncology." He also indicates that the results related to the effect of IL-6 and FGF-2 blockade on obesity-related anti-VEGF resistance could be clinically tested soon as most of the inhibitor pathways are already available. A drug called metformin (type-2 diabetes drug) was used to block FGF-2, it also suppresses the growth of certain cancers.
Co-senior author Dai Fukumura, MD, PhD, deputy director of the Steele Labs, says, "Although the role of systemic adipokines - signaling molecules derived from adipose tissues - has been studied in multiple obesity-associated diseases, studies dissecting their role in cancer have been limited. Our studies are the first to demonstrate the role of the adipokines IL-6 and FGF-2 in both breast cancer patients and clinically relevant animal models and that these adipokines are derived from adipocytes within tumors. There are many different adipokines, and we found that different factors mediate anti-VEGF resistance in different subsets of breast cancers. Investigations of the crosstalk between cancer-associated adipocytes and the tumor microenvironment are needed to develop novel strategies to overcome obesity-induced aggravation of breast cancer."
About Breast Cancer
Breast cancer is the most common type of cancer occurring in women and the most common symptoms of the cancer are a lump in the breast, reddening of the breast skin, inverted nipple, scaling of the skin around the nipple region and change in shape of the breast. Breast cancer can be diagnosed by different methods like biopsy, mammogram, breast examination and MRI. Treatment involves the surgical removal of either the tumor or the entire breast and radiation therapy.
- Joao Incio, Jennifer A. Ligibel, Daniel T. McManus, Priya Suboj, Keehoon Jung, Kosuke Kawaguchi1, Matthias Pinter, Suboj Babykutty, Shan M. Chin1, Trupti D. Vardam1, Yuhui Huang, Nuh N. Rahbari, Sylvie Roberge1, Dannie Wang, Igor L. Gomes-Santos, Stefan B. Puchner, Christopher L. Schlett, Udo Hoffmman, Marek Ancukiewicz , Sara M. Tolaney, Ian E. Krop, Dan G. Duda, Yves Boucher, Dai Fukumura, and Rakesh K. Jain,. Obesity promotes resistance to anti-VEGF therapy in breast cancer by up-regulating IL-6 and potentially FGF-2Science Translational Medicine,(2018)