Clinical Relevance of Needle Biopsy-Induced Prometastatic Phenotypic Changes in Breast Cancer
Abstract
Delay of breast cancer (BC) surgery has become increasingly common over the past decades in the U.S. A group of investigators, including us, have raised concerns about the increased risk of disease progression and mortality for early-stage BC patients who wait for surgery over 60 days after diagnosis. Accordingly, the American College of Surgeons Commission on Cancer introduced a new recommendation for therapeutic surgery within 60 days of diagnostic biopsy, effective in 2023. A question remains, however, as to what causes such rapid disease progression that can negatively impact survival among generally good prognostic early-stage breast cancer. Currently, no biological mechanisms explain the risk of rapid increase in mortality after diagnostic biopsy. Our funded Breakthrough Award developed a radically novel, paradigm-shifting concept that needle biopsy provokes progressive prometastatic changes that lead to systemic dissemination of breast cancer. Successful completion of the project provided coherent evidence to support this novel concept: (1) biopsy of tumor leaves an unhealed wound dominated by prometastatic M2 macrophages that concomitantly promote the phenotypic conversion of BC cells, angiogenesis, and metastasis; (2) sustained elevation of cyclooxygenase-2 (COX-2) cascade in the wound stroma, accompanied by low oxygen hypoxia tension, favor M2 macrophage dominance; and (3) oral administration of COX-2 inhibitors alleviate biopsy-induced metastasis. In addition, our epidemiologic analysis showed the emergence of a conspicuous increase of mortality risk at 53 days after needle biopsy that followed by an exponential rise, growing from 6% to 30% higher risk each subsequent week, which translates to approximately 5-, 24-, and 54-times higher mortality rates over a 14-year period for patients with biopsy-to-surgery intervals of 60, 90, and 120 days, respectively, compared to those who had surgery within 30 days of diagnosis. Our funded project concept is contrary to the current clinical dogma and altered the prevailing view of (1) the absolute safety of needle biopsy, and (2) the contraindication of nonsteroidal anti-inflammatory drugs (NSAIDs) after biopsy. How has the mortality risk associated with needle biopsy been overlooked this long? Early studies conducted in the 1960s to 1980s granted the safety of needle biopsy, although the average biopsy-to-surgery interval used in those studies was 7 to 30 days, well within the risk-free first 53 days in our study. Therefore, such risk was previously undetected. However, soaring treatment delays beyond the safety window in the modern U.S. clinical setting has uncovered increased mortality risk associated with surgery delay after biopsy. Thus, the new recommendation for timely surgery undoubtedly alleviates the mortality risk posed by surgery delay; however, significant challenges remain since many delayed cases are involuntary. Our cohort analysis showed disproportionate surgery delay in racial minorities, socioeconomically disadvantaged women, and those needing additional medical procedures. For example, first-time enrollment in Medicaid for qualifying, newly diagnosed women in Oklahoma typically takes up 7 to 8 weeks before surgery can be approved (depending on the state of residence), and the average wait time for surgery in one well-regarded cancer center is 11 weeks since the vast majority of their patients have sought second opinions there. With the diverse causes of surgery delay, the recommendation of a timeline does not simply solve the issue; and there remains a current pressing need to implement a safe, affordable prevention strategy for post-biopsy care to mitigate negative effects in patients for whom delay may be unavoidable. Leveraging the preclinical data obtained in the Breakthrough Award, the Expansion Award seeks to advance the clinical relevance of this problem. Using 100 surgically resected clinical BC cases and their matche
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310710
Entities
People
- Takemi Tanaka
Organizations
- United States Army
- University of Oklahoma Health Sciences Center