Week 4

This week I focused on academic pursuits and started to look more in-depth at the molecular aspects of radiotherapy (RT). Since my research in Ithaca involves establishing a relationship between molecular changes to bone and bone-metastatic potential of breast cancer, it makes sense to incorporate that expertise into studying RT. External beam RT works by shooting ionizing radiation (high-energy X-Rays or gamma-rays) into a tissue where energy is deposited, leading to the production of free radicals that cause DNA damage and interrupt cell-cycle progression. 

This DNA damage elicits a response from the affected healthy tissues surrounding the tumor, incorporating cell signaling from soluble factors like growth factors, chemokines, and cytokines, as well as remodeling of the extra-cellular matrix (ECM) by induction of proteases, growth factors, and the production of reactive oxygen species (ROS). Hydroxide ions, which are the primary free radicals generated by RT are also a ROS, and can contribute to ECM remodeling even without a corresponding damage response. 

Additionally, I looked into the local bone microenvironmental effects of RT at therapeutic dosages. After RT, studies have identified persistent remodeling of the ECM including a loss of hyaluronic acid, collagen remodeling, and changes in collagen production in irradiated cells. Bones of mice irradiated in one study showed a chronic loss of mesenchymal stem cells in the irradiated area, a three-fold increase of free radicals, loss of vasculature, and decreased numbers of osteoclasts and osteoblasts. 

In the clinic, I shadowed Dr. Ng and saw numerous patient consults, follow-ups, sims, and treatments. I saw a few patients with DCIS who had lumpectomies, were starting courses of hormone therapy (usually Tamoxifen), and were referred to the clinic for whole breast RT. This is the standard of care for premalignancies in breast. The role of the RT in this regimen is to catch any local microscopic disease not captured during surgery or not detected by imaging, preventing local recurrence. This treatment is so effective that patients have a lower risk of disease recurrence in the ipsilateral breast than the risk of de novo DCIS in the general population (or in their untreated contralateral breast). 

On the other end of the spectrum, I saw patients with recurrent disease who were in the clinic for palliative RT of bone metastases. Some of these patients were as many as thirty years from their initial breast cancer diagnosis and as far as fifteen years from their diagnosis of recurrent breast cancer. Many of these patients were elderly, but some were very young. Depending on their age and comorbidities, these patients were on various medical treatments for their metastatic disease. Some were on bisphosphonates to control the osteolysis caused by their bone mets. Others were on Denosumab, a RANKL monoclonal antibody aimed at controlling osteoclastic differentiation and osteolysis. Because most of these patients had estrogen receptor (ER)-positive diagnoses, they were also on Letrozole or another aromatase inhibitor (AI), which aims to prevent aromatase from converting androgen into estrogen, thereby starving the cancer cells of hormone signaling. Importantly, I learned that doctors do not give AIs to premenopausal women, even in conjunction with an anti-estrogen like Tamoxifen, because premenopausal women have high levels of aromatase substrate in their ovaries, which respond rapidly to AI administration by producing even more substrate.