Diagnostic Diversity and Heterogeneity of Tumors: A Real-World Study of Metastasis Re-Biopsy in Advanced Breast Cancer
Breast cancer remains one of the most prevalent malignancies among women globally. Despite advancements in diagnostic and therapeutic technologies, which have contributed to a decline in recurrence and mortality rates, metastatic breast cancer (MBC) continues to pose significant challenges. Metastatic breast cancer is considered incurable, and its treatment is complex, particularly after the failure of first-line therapies. Breast cancer is characterized by its heterogeneity, with variations in the expression levels of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), which are critical biomarkers for clinical decision-making and prognosis.
This study aimed to explore the diagnostic diversity and inconsistencies in ER, PR, and HER2 expression levels between primary and metastatic lesions in advanced breast cancer (ABC) patients. The research was conducted through a retrospective analysis of 1670 ABC patients who underwent at least one re-biopsy of metastatic lesions between January 2010 and December 2018. The study collected data on pathological diagnoses, biopsy site distributions, and severe puncture complications. Additionally, it analyzed the inconsistency rates and related factors of ER, PR, and HER2 expression between primary and metastatic lesions, taking into account patients’ demographic profiles and disease characteristics.
The study included 1670 breast cancer patients who underwent one to four biopsies of recurrences or metastases at different sites or stages during rescue treatment, resulting in 2019 histopathological specimens. Pathological diagnoses revealed that eight patients had benign lesions, 11 had second primary malignant tumors without breast cancer recurrence, and 17 had breast cancer recurrences combined with second primary cancers. Among 1173 patients with available ER, PR, and HER2 expression data for both primary and metastatic lesions, the inconsistency rates were 17.5% for ER, 31.3% for PR, and 13.9% for HER2. Multivariate analysis identified the age at breast cancer onset and adjuvant endocrine therapy as independent factors affecting changes in PR expression levels. The study reported minimal severe puncture complications, with only one case of local hemorrhage during liver biopsy and two cases of hemopneumothorax during lung biopsies among 1950 non-surgical re-biopsies.
The findings underscore the diagnostic diversity and heterogeneity in ER, PR, and HER2 expression levels between primary and metastatic lesions in ABC patients. The study highlights the importance of routine biopsies in relapsed and metastatic breast cancers to guide treatment decisions and improve patient outcomes. The safety and feasibility of biopsy procedures, including those for visceral metastases, were also confirmed, supporting their broader application in clinical practice.
Breast cancer’s heterogeneity necessitates stratification of tumors to achieve better clinical outcomes. Tumor heterogeneity refers to the existence of subpopulations of cells within a primary tumor and its metastases that have distinct genotypes and phenotypes, leading to varied biological behaviors. Previous studies have confirmed that re-biopsy of breast cancer recurrence and metastasis can confirm pathological diagnoses, exclude second primary tumors, clarify changes in hormone receptor and HER2 status, and guide treatment plans. This study further validated these findings, detecting 19 cases where breast cancer recurrences were ruled out and 28 cases of second primary tumors, including 18 lung cancers and three ovarian cancers. The presence of second primary cancers in breast cancer patients emphasizes the need for differential diagnosis in ABC.
The study also confirmed the inconsistency in ER, PR, and HER2 expression levels between primary and metastatic lesions, with inconsistency rates of 17.5%, 31.3%, and 13.9%, respectively. These discrepancies may result from tumor tissue heterogeneity, clonal selection of tumor cells, tissue fixation, antigen repair, differences in staining methods, subjective judgment of technicians, tumor microenvironment, and previous treatments. The study noted that 48.0% of primary lesion results were reported by other hospitals, while most metastatic lesion results were reported by the study hospital, potentially introducing bias. The long interval between primary tumor and metastasis detection also raises questions about whether inconsistencies are due to long-term clonal selection or detection errors.
Previous studies on factors contributing to inconsistencies in ER, PR, and HER2 expression levels have been inconclusive. Some suggest that previous anthracycline-based chemotherapy makes ER expression more susceptible to change, while others indicate that endocrine therapy after chemotherapy leads to higher rates of PR expression changes. This study found that young patients (aged ≤35 years) or those who received adjuvant endocrine therapy had higher rates of PR expression changes. No factors correlated with changes in ER or HER2 expression levels, consistent with previous studies. However, these findings require further validation through prospective studies.
The study also explored the inconsistency rates of ER, PR, and HER2 in different metastatic sites. While some studies suggest that temporal and spatial heterogeneity between primary tumors and metastases result in different inconsistency rates in different metastatic sites, this study found no significant differences in inconsistency rates across metastatic sites. The safety and feasibility of biopsy procedures for visceral metastases were confirmed, with minimal complications reported.
The study has several limitations, including its retrospective design, lack of a standard operating procedure for metastasis biopsy, and potential selection biases in patient compliance, biopsy site determination, and biopsy method. The proportion of adverse events may be underestimated, as not all events were recorded. Additionally, follow-up information for patients diagnosed with second primary cancers was lacking, as they were transferred to other departments for treatment.
Despite these limitations, the study underscores the importance of re-biopsy in metastatic breast cancer to confirm pathological diagnoses, exclude second primary tumors, and clarify changes in ER, PR, and HER2 status. The findings support the routine use of biopsies in clinical practice to guide treatment planning and prognostic evaluation for metastatic breast cancer. The safety and feasibility of biopsy procedures, including those for visceral metastases, were also confirmed, supporting their broader application in clinical practice.
In conclusion, this study highlights the diagnostic diversity and heterogeneity in ER, PR, and HER2 expression levels between primary and metastatic lesions in ABC patients. The presence of second primary cancers in breast cancer patients emphasizes the need for differential diagnosis in ABC. The findings support the routine use of biopsies in clinical practice to guide treatment planning and prognostic evaluation for metastatic breast cancer. The safety and feasibility of biopsy procedures, including those for visceral metastases, were also confirmed, supporting their broader application in clinical practice.
doi.org/10.1097/CM9.0000000000001969
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