New Research From SAB Members Dr. Sikora and Dr. Stover – Lay Summaries and Q&A
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LBCA Scientific Advisory Board (SAB) members Dr. Matt Sikora and Dr. Daniel Stover both have recent studies on lobular breast cancer. Below are lay summaries of each of the two research studies followed by and a Q&A with patient advocates to help further understanding.
Research Spotlight: Could Radiation Be an Underused Ally in Treating ILC?
A recent article
by a member of the LBCA Scientific Advisory Board explores how the biology of ILC may make it particularly sensitive to radiation therapy.
Study Summary
This review of published clinical data highlights that ILC may be particularly sensitive to ionizing radiation therapy (XRT). The benefits of XRT specifically for patients with ILC have been unclear for two major reasons. First, clinical trials of XRT to date have not prospectively considered tumor histology (i.e. considered ILC as a design factor for the trial), and only a limited number have retrospectively examined histology in the trial results (i.e. re-examined tumors to identify ILC after study completion). Second, the unique discohesive, single-file growth pattern of ILC has led to a presumption that ILC should be treated with whole breast irradiation (WBI) but not partial breast irradiation (PBI). Given these gaps in understanding, the authors re-evaluated published studies to explore our current understanding of XRT response in ILC.
The authors found that studies to date support that XRT, in particular WBI, substantially reduces disease recurrence and improves overall survival for ILC. However, XRT is underutilized to treat patients with ILC, suggesting XRT may be yet better applied for patients with ILC. Though available data on PBI was limited due to evolving PBI modes over time, appropriate application of PBI similarly reduced disease recurrence for ILC. Though the available data support that XRT is likely very effective for ILC, the authors noted that without prospective data, current treatment guidelines largely exclude ILC from consideration from PBI and offer no specific recommendations for XRT use.
The review highlights recent laboratory research suggesting that XRT sensitivity may stem from specific deficiencies in how ILC cells repair DNA damage, making them more susceptible to radiation. Research to understand this DNA repair deficiency is ongoing and could lead to tailored use of XRT and radio-sensitization approaches for ILC.
Why this Matters: This review highlights that XRT may be highly effective yet underutilized for ILC. These findings support the need for ILC-specific research and clinical trial design in the use of XRT, which could support ILC-specific treatment recommendations for XRT use.
Question: If PBI could be confidently administered (i.e., evidence suggesting similar outcomes to WBI for appropriate cases), what would be the biggest benefits to patients?
The primary benefit to PBI for patients is reduced dose and toxicity to the skin, normal breast tissue, and surrounding organs.
Question: Is the use of radiation therapy contemplated more broadly in mLBC such as radionucleotide targeting of metastatic sites?
An important limitation we noted in this review was that we could not identify any published outcomes data for patients with metastatic ILC. Combined with the frequent exclusion of mILC from clinical trials, this is a serious deficiency in the field.
Question: Can a lower dose of radiation be given to LBC patients to achieve the same tumor response, thereby decreasing radiation toxicity?
A goal of our research would be to identify whether DNA repair deficiency would indeed correlate with hypersensitivity to XRT, as an indicator for dose-reduction. At present there is no clinical data to support dose reduction, for lack of study.
Question: Has the role of dysfunctional DNA repair in ILC been confirmed in multiple pre-clinical studies?
Work from the Sikora Lab supports that this dysfunction may be particularly prevalent in high-risk ILC, as we see evidence of the dysfunction in ILC tumor data that mirrors preclinical studies. Replication of our findings by other groups will be important for future work
New Clues on Why Some ILCs Become Resistant to Tamoxifen
This laboratory study co-authored by Dr. Stover, sought to understand why some ILC tumors stop responding to tamoxifen, a type of endocrine therapy that many ILC patients receive.
Tamoxifen is a commonly used drug to treat patients who are hormone receptor positive. Researchers uncovered a novel mechanism behind tamoxifen resistance in invasive lobular carcinoma (ILC). Prolonged tamoxifen treatment led to reduction in argininosuccinate synthase 1 (ASS1) level, an enzyme involved in production of the amino acid arginine, required for making protein in the human body. This alteration appears to drive changes in cancer cell metabolism allowing to make more of the nucleic acids required for DNA synthesis. This promotes survival and faster growth of the cells even in presence of the drug that is supposed to kill them. Restoring ASS1 levels or inhibiting nucleotide synthesis helped re-sensitize ILC cells to tamoxifen, pointing to possible new treatment strategies.
Overview: This laboratory study used multi-omics approaches (combining gene expression, and metabolic profiling) to understand why some ILC tumors stop responding to tamoxifen, a type of endocrine therapy that many ILC patients receive. Two ILC cell lines were made resistant to tamoxifen (called TAMR), and then researchers investigated how these cells changed on a molecular level compared to parent (non-resistant) cells.
Key Findings
Loss of ASS1 expression: The resistant ILC cells had much lower levels of ASS1. This enzyme is important in cellular metabolism, specifically in the production of arginine.
Increased nucleotide biosynthesis: The resistant cells showed increased production of molecules needed to make DNA and RNA—suggesting a shift in metabolic activity that supports continued growth despite tamoxifen.
Therapeutic potential: When researchers either restored ASS1 expression or blocked nucleotide production, the tamoxifen-resistant cells became more sensitive to tamoxifen again.
Why This Matters: The study suggests that loss of ASS1 and increased nucleotide biosynthesis (building blocks of DNA and RNA) may play a key role in how some ILC tumors escape the effects of tamoxifen. These findings point to potential new treatment strategies—such as combining tamoxifen with drugs that restore ASS1 activity or inhibit nucleotide synthesis.
What the Authors Recommend
Additional research to confirm ASS1’s role as a predictive biomarker in ILC.
Further exploration of therapies targeting metabolic vulnerabilities in tamoxifen-resistant ILC, using lab-based models.
Questions from Advocates for Dr. Stover and Colleagues
Question:This study utilized ILC cell lines to demonstrate mechanisms of tamoxifen resistance in ILC. What are the likely next steps for moving these findings from the lab to the clinic? Or in other words, how will your findings be translated to clinical practice with patients?
Answer: Our next steps will focus on analyzing patient tumor samples and seeing if ASS1 can identify patients who could receive tailored therapy based on ASS1 results.
Question:You found that ASS1 can “turn off”, which leads to resistance to tamoxifen. But a demethylating drug (Decitabine) “turned back on” ASS1 and the cells became more sensitive to tamoxifen again. Is your hypothesis that needs to be tested in humans that, for patients who are taking tamoxifen, something like Decitabine could be prescribed alongside tamoxifen to keep cells from becoming resistant or given once resistance is detected in order to make the tamoxifen effective again?
Answer: Our conclusions are mostly from laboratory/cell line studies and mouse studies will be the next priority. Decitabine is a possibility but with known (challenging) side effects, we are looking into better tolerated, more targeted ways to go after the unique vulnerabilities that these cells have.
Question:Acknowledging that resistance can develop, is there research underway that would help patients who take tamoxifen to check for potential drug resistance?
Answer: Yes, multiple approaches to check for potential drug resistance are underway in collaboration with Bioengineering department at The Ohio State University. Dormant Cancer Cells (DTCs), and Circuating Tumor Cells (CTCs) provide clues as cancer evolves with time and treatment. We are studying CTCs in plasma samples of ILC patients retrospectively and plan to collect blood from prospective patients at regular intervals for future studies. We believe these studies will provide us with clues and markers to detect development of resistance before disease recures.
Question:Do the findings of this study suggest that a similar mechanism could be at play for patients on aromatase inhibitors? Furthermore, if lobular breast cancer patients treated initially with Tamoxifen are found to be resistant, and then switch to treatment with AIs, would you hypothesize that they are still expected to have poor outcomes?
Answer: Although our current findings are specific to tamoxifen resistance in ILC cells, we believe lack of estrogen/estrogen signaling plays a key role in reducing ASS1. We are investigating of other anti-estrogens, like aromatase inhibitors or fulvestrant, could ‘turn off” ASS1, or whether this is specific to tamoxifen.
Question:When you have resistant cells, have you explored ways, such as increasing the amount of tamoxifen, to get an improved therapeutic effect?
Answer: Yes, the resistant cells are still sensitive to tamoxifen but at a significantly higher dosage. The amount of tamoxifen required to inhibit the tamoxifen resistant cells (IC50 or Inhibitory concentration at 50%) is double that of the sensitive cells. Higher dosage of the drug has the potential of higher toxicity and thus finding a combination therapy to improve efficacy of tamoxifen is our goal.
Question:Did your study indicate how quickly tamoxifen resistance occurs? How will this be translated from cell line research to human studies?
Answer: In our in vitro studies, tamoxifen resistance developed gradually over 6 months when the cells were continuously exposed to tamoxifen. This reflects the progressive nature of resistance, but the exact timing in patients is expected to vary widely depending on multiple factors and cannot be directly predicted from in vitro experiments. Studies using cell lines revealed one of the ways tamoxifen changes cancer cells to evade the drug. Follow up preclinical and clinical studies to determine whether similar molecular changes occur in patients and to use the identified gene/protein as biomarkers will be helpful to monitor resistance as it emerges.
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