Editor’s Note: Breast diseases have the highest incidence among women, with breast cancer being the leading malignant tumor threatening women’s health. From “one-size-fits-all” treatments to “individualized therapy” based on patients, the exploration of breast cancer treatment has been ongoing for centuries. At the 2024 South-North Forum, Prof. Zhiming Shao from Fudan University Cancer Hospital presented a report titled “Precision Typing Drives Diagnosis and Treatment Innovation: A New Model for Breast Cancer Precision Diagnosis and Treatment.” This article introduces the key points of the report.
Four Revolutions in Breast Cancer Diagnosis and Treatment
First Revolution: Surgical Treatment
Initially, breast cancer was considered a localized disease, with surgery being the primary treatment. In 1894, William Halsted introduced the radical mastectomy (Halsted procedure), which improved effectiveness and reduced cancer recurrence in surrounding tissues compared to previous surgical methods, marking a milestone in the history of breast cancer treatment.
Second Revolution: Systemic Treatment
It gradually became understood that breast cancer is a systemic disease, and systemic chemotherapy could improve patient outcomes. In the 1970s, Professors Bernard Fisher and Veronesi simultaneously discovered that breast cancer could metastasize to lymph nodes and the bloodstream, leading to the realization that systemic chemotherapy could enhance patient outcomes.
Third Revolution: Typing Treatment
The limited benefits of “one-size-fits-all” systemic treatment led to the development of molecular typing research. At the end of the last century, renowned American biologist Charles M. Perou classified breast cancer into Luminal, Triple-negative, and HER2-positive subtypes based on expression profiles, and corresponding treatments were developed. While the prognosis for HER2-positive breast cancer improved significantly, the prognosis for other subtypes improved only modestly.
Fourth Revolution: Precision Typing Treatment
The future of breast cancer treatment will move towards precision typing treatment. Precision typing treatment involves further subtyping within molecular types or identifying unique targets within subtypes for corresponding treatments. This model, characterized by “broad population coverage and high specificity,” is expected to revolutionize patient treatment.
Establishing a New Model for Precision Typing Treatment of Breast Cancer
Focusing on Chinese Patients and Mapping Profiles
The incidence of breast cancer varies significantly with age, race, and region. For example, the high-risk age group for breast cancer in China differs significantly from Western countries. In Western countries, two-thirds of breast cancer cases occur in postmenopausal women, with the incidence increasing with age. In contrast, China exhibits a “double peak” pattern: one peak at 45-55 years and another at 65-75 years.
Currently, most multi-omics cohorts are predominantly Caucasian, lacking large-scale cohorts of Chinese populations. Additionally, the current multi-omics cohorts often lack large-scale proteomics and metabolomics data, making it difficult to apply these results clinically. Therefore, developing a precision diagnosis and treatment strategy tailored to the Chinese population is essential.
Against this backdrop, Prof. Zhiming Shao and Researcher Yizhou Jiang from Fudan University Cancer Hospital, in collaboration with domestic experts, spent five years systematically analyzing genomic, transcriptomic, proteomic, metabolomic, radiomic, and digital pathology characteristics. Building on previous multi-omics studies of triple-negative breast cancer, they established the largest natural multi-omics cohort of Chinese breast cancer to date, comprehensively revealing the molecular characteristics of Chinese breast cancer (China Breast Cancer Genome Atlas, CBCGA).
This cohort is the largest Asian cohort with the most comprehensive multi-omics data, revealing unique multi-omics features of Asian breast cancer and identifying clinical diagnostic and therapeutic clues.
Key Findings:
1. Genomic Differences: Chinese breast cancer patients have a higher frequency of AKT1 mutations (6.4% vs. 2.5%, FDR=0.032) compared to Western patients, with the most significant difference in Luminal A subtype (12.1% vs. 4.4%, FDR=0.025). AKT1 has hotspot mutations like E17K, indicating that Chinese Luminal A breast cancer patients might benefit more from targeted AKT therapy.
2. HER2-enriched Subtype: In the overall population and HR+/HER2+ clinical subtype, Chinese patients have a higher proportion of the HER2-enriched subtype (PAM50) compared to Caucasian patients. Comparing PEONY and NeoSphere clinical trials, Chinese HR+/HER2+ breast cancer patients showed higher efficacy with dual-targeted therapy, with less difference in efficacy between HR+/HER2+ and HR-/HER2+ breast cancer. This suggests higher sensitivity to anti-HER2 targeted therapy among Chinese HR+/HER2+ breast cancer patients.
3. Metabolomic Differences: Different subtypes of breast cancer showed unique metabolic disorders compared to normal breast tissue. Basal-like subtype is enriched in ferroptosis-related lipid peroxidation and proteins, indicating higher sensitivity to ferroptosis inducers, providing potential targets for future precise treatments.
Overall, the CBCGA study offers a comprehensive multi-omics cohort and provides extensive data from genomic, transcriptomic, proteomic, metabolomic, radiomic, and digital pathology perspectives. This dataset helps identify potential therapeutic targets, racial differences, tumor microenvironment characteristics, and metabolic features, serving as a critical reference for future research on the biological complexity of breast cancer.
Breaking Through Triple-Negative Breast Cancer with “Fudan Typing”
“Fudan Typing” is a series of precision typing studies in triple-negative breast cancer, forming a closed-loop research system from clinical practice to basic research and back to clinical application. Prof. Shao’s team has optimized and expanded the treatment of triple-negative breast cancer, continuously enriching the connotation of “Fudan Typing,” with related results published in high-quality international journals (e.g., Cancer Cell, Cell Res, Cell Metab). They have developed a clinically practical typing kit, authorized national invention patents, and achieved successful commercialization, yielding significant economic benefits. “Fudan Typing” has successfully validated the scientific integration of multi-omics molecular typing and established a mature translational research system.
Expanding Subtypes for Comprehensive Coverage
Prof. Shao’s team has achieved significant accomplishments in late-stage triple-negative breast cancer by adhering to the concept of precision typing. The FUTURE series of clinical studies demonstrated substantial patient benefits. The FUTURE-C-Plus study included 48 IM-type late-stage triple-negative breast cancer patients, with a median follow-up of 33.1 months. The results showed an objective response rate (ORR) of 81.3% (95% CI: 70.2-92.3), median PFS of 13.6 months (95% CI: 8.4-18.8), median OS of 29.4 months (95% CI: 23.3-35.5), and disease control rate of 95.8% (46/48), with controllable safety. The study was presented orally at the 2021 ASCO Annual Meeting, published in Clin Cancer Res in 2022, and featured again at the 2023 ASCO Annual Meeting. The FUTURE-C-Plus study significantly extended PFS and OS, providing new hope for more patients.
FUTURE-SUPER is an umbrella randomized Phase II study comparing the efficacy of first-line precision treatment based on different subtypes with standard chemotherapy in metastatic TNBC. The study included 139 patients, randomly assigned to the precision treatment group (n=69) and the standard treatment group (n=70). Results presented at the 2023 ASCO conference showed that the median PFS in the precision treatment group was significantly longer than in the standard treatment group (11.3 months vs. 5.8 months), with a significantly higher ORR (80.0% vs. 44.8%, OR=0.20).
Series of clinical trials have achieved comprehensive precision typing coverage, significantly improving patient outcomes. Additionally, FUTURE-SUPER 2.0 and multiple Phase III clinical trials are ongoing, anticipating early publication of results to further advance precision treatment for triple-negative breast cancer.
Expanding to Luminal-Type Breast Cancer
Prof. Shao highlighted that compared to other subtypes, Luminal-type breast cancer has a long-term recurrence risk, with a significant proportion recurring ten years or more after surgery. Currently, the treatment approach for Luminal-type breast cancer involves extended endocrine therapy or precision treatment for the entire population. Key issues include unclear molecular nature and insufficiently precise treatment, leading to limited efficacy improvements. To address these issues, Prof. Shao and Prof. Jiang’s team initiated precision treatment based on molecular typing for Luminal-type breast cancer, leveraging CBCGA data and experience from treating triple-negative breast cancer.
Steps Taken:
1. Precision Strategy Based on Molecular Typing: Constructing the largest Chinese breast cancer multi-omics natural cohort (n=773) to reveal molecular characteristics comprehensively. Focusing on key clinical issues in Luminal-type breast cancer, constructing a multi-omics cohort (n=579) including genomic, transcriptomic, metabolomic, and single-cell dimensions. Results were presented at the 2023 ESMO and SABCS conferences.
2. Artificial Intelligence Implementation: Using AI to assist in solving clinical problems quickly and accurately. Conducting AI combined with digital pathology and radiomics research for rapid, accurate realization of “Fudan Typing” and target visualization for triple-negative breast cancer. Related research has received significant funding from the National Natural Science Foundation twice. Additionally, Prof. Shao’s team designed algorithms and constructed predictive models based on deep learning and other AI technologies.
3. Collaborative Clinical Research: Establishing a multi-center breast cancer precision treatment collaboration group (BCTOP) to conduct clinical trials on precision typing
treatment. Through multi-center collaboration, conducting clinical research (real-world studies, prospective clinical trials) to validate the efficacy of precision treatment for Luminal-type breast cancer. Retrospective studies of real-world cohorts demonstrated the relationship between SNF typing and clinical pathological characteristics, prognosis, and efficacy. Results showed that in the late-stage multi-center cohort, the proportion of SNF1 decreased significantly, while SNF4 increased. SNF3 was sensitive to CDK4/6 inhibitors, and SNF4 was sensitive to TKI treatment. Currently, precision treatment efficacy is significantly better than traditional treatment in the CDK4/6 inhibitor progress group.
Conclusion
Breast cancer exhibits heterogeneity, and current treatment approaches face various clinical challenges, necessitating optimization of existing strategies. Precision treatment based on molecular typing, through multi-center collaborative clinical research, is significant for changing clinical practice and addressing heterogeneity. The precision treatment concept-guided approach for breast cancer patients is expected to lead to a new transformation in breast cancer diagnosis and treatment models.
Prof. Zhiming Shao
– Professor at Fudan University Cancer Hospital
– First batch of Ministry of Education Changjiang Scholars Distinguished Professors
– 2000 National Science Fund for Distinguished Young Scholars recipient
– Fudan University Distinguished Professor
– Director of Fudan University Cancer Institute and Fudan University Breast Cancer Institute
– Director of the General Surgery Department and Breast Surgery Department at Fudan University Cancer Hospital
– Honorary Director of the Breast Cancer Professional Committee of the Chinese Anti-Cancer Association
– Former Director of the Tumor Targeted Therapy Professional Committee of the Chinese Anti-Cancer Association
– Director of the Chinese Society of Clinical Oncology
– Deputy Director of the Oncology Branch of the Chinese Medical Association
– Group Leader of the Breast Cancer Group of the Clinical Precision Medicine Professional Committee of the Chinese Medical Doctor Association
– Vice President of the Shanghai Anti-Cancer Association
– Former Director of the Breast Cancer Professional Committee of the Shanghai Anti-Cancer Association
– Honorary Director of the Oncology Specialty Committee of the Shanghai Medical Association
– Eighth President of the Asian Breast Cancer Society
– Published nearly 500 papers on breast cancer research, with over 400 included in SCI, and authored 10 books
– Editor-in-Chief of the Chinese Journal of Cancer
– Recipient of multiple national, ministerial, and municipal science and technology progress awards
