Researchers at the Johns Hopkins Kimmel Cancer Center and its Bloomberg~Kimmel Institute for Cancer Immunotherapy have released updated consensus guidelines and an associated reproducibility study to standardize how pathologists assess tumor response to neoadjuvant therapy (administered prior to surgery) across a dozen solid tumor types.
The work was funded in part by the National Institutes of Health and The Mark Foundation, and it was completed in collaboration with the Society for Immunotherapy of Cancer (SITC) and the International Neoadjuvant Melanoma Consortium (INMC).
The recommendations, published Nov. 4 in Annals of Oncology , provide the first unified, pan-tumor framework for evaluating residual viable tumor (RVT, the amount of cancer cells remaining), necrosis (cancer cell death) and regression (a constellation of histologic findings that includes inflammation and features of wound healing) after presurgical treatment. They refine and expand earlier immune-related criteria first proposed in lung cancer in 2018, and in a pan-tumor fashion in 2020, which are now updated based on five years of real-world use, questions from the field and new reproducibility data. A related reproducibility study , published Feb. 2 in Annals of Oncology, found that the tumor guidelines can be applied across many different tumor types and achieve consistent results when used by different pathologists around the world.
"Neoadjuvant therapy is rapidly expanding across cancer types, and pathologic response is emerging as a predictor of long-term survival and an important clinical trial endpoint," says lead author Julie Stein Deutsch, M.D. , assistant professor of dermatology, pathology and oncology. "However, scoring systems have varied widely by tumor type, making it difficult to compare across studies or apply results reliably in practice. This unified approach establishes a common language that will benefit clinical care, research and future regulatory use."
The updated framework was prompted by growing evidence that tissue changes seen under a microscope that indicate a cancer is shrinking or responding to treatment — particularly after immunotherapy — appear remarkably consistent across cancers. The research team previously reviewed about 500 specimens treated with anti-PD-1 immunotherapy drugs alone or in combination with other agents (such as chemotherapy or targeted therapy) and observed similar patterns of response regardless of tumor origin. John Hopkins Kimmel Cancer Center investigators worked with SITC and INMC to create a single, harmonized standard, recognizing that parallel systems risked confusion and limited comparability.
"Most pathologists around the world are generalists, not tumor-type specialists," says senior author Janis Taube, M.D. , director of dermatopathology and co-director of the Bloomberg~Kimmel Institute tumor microenvironment laboratory. "Switching between multiple scoring systems is inefficient and can lead to inconsistent reporting. Our findings support a pan-tumor system — and importantly, no existing tumor-specific system outperforms this unified approach in predicting patient outcomes."
A major advance with the new guidelines is their demonstrated reproducibility, the researchers say. In a multi-institutional, international study involving 14 pathologists, RVT scoring using the updated criteria proved highly reproducible after a short, standardized training session. Using the standardized criteria, pathologists demonstrated high concordance in scoring RVT, regression and necrosis, regardless of tumor type, anatomic location or whether the specimen was a surgical resection or biopsy. The findings were presented at the American Society of Clinical Oncology annual meeting in 2024. These findings reinforce the rationale for a unified, pan-tumor approach to pathologic response assessment comparable to Response Evaluation Criteria in Solid Tumors (RECIST), the standard method doctors use to measure how tumors change in size on imaging scans, and provide a validated foundation for standardized data collection as neoadjuvant (therapy given before surgery) and perioperative (therapy given before and after surgery) approaches continue to expand across cancer types, the researchers say.
"Reproducibility is essential," says Deutsch. "Different pathologists must arrive at similar scores if these metrics are going to guide patient care and clinical trials. Our training materials make that possible, and we are partnering with SITC to disseminate these resources." The researchers say next steps include refining clinically meaningful RVT thresholds for specific tumor types as additional survival data become available.
In addition to Taube and Deutsch, other researchers participating in the studies were Tricia Cottrell, Richard Scolyer, Ezra Baraban, Pierre Oliver Fiset, Jaroslaw Jedrych, Christine Orr, Francisco Real, Roberto Salgado, E. Burton, K.J. Busam, Krista Chen, Ashley Cimino-Mathews, C.E. de Andrea., G.V. Long, J. Messina, R.V. Rawson, Christian Schurch, Raja Seethala, Lynette Sholl, Sabina Signoretti, Suzanne Topalian, B.A. van de Weil, Xiaowei. Xu, J.E. Gershenwald, Michael Tetzlaff, Hao Wang, Tingchang Wang, Annikka Weissferdt and James Ziai.
The work was supported by The Mark Foundation for Cancer Research, the Bloomberg~Kimmel Institute for Cancer Immunotherapy, the Ontario Institute for Cancer Research, and National Institutes of Health/National Cancer Institute grants R01CA142779, The National Institutes of Health Specialized Programs of Research Excellence melanoma grant P50 CA93459, the University of Texas MD Anderson Melanoma Moon Shots Program, LUNGevity Foundation, the Dermatology Foundation, Australia's National Health and Medical Research Council, University of Sydney Medical Foundation, the Michael and Patricia Booker Melanoma Research Endowment and the John M. Skibber Endowed Professorship.
The researchers disclose the following: Deutsch is a consultant for NextPoint therapeutics. Taube is a consultant/advisory board member for Bristol Myers Squibb, Merck & Co, Moderna, Astra Zeneca, Roche, Regeneron, Elephas, Quanterix, NextPoint and Compugen. She receives institutional research funding from Bristol Myers Squibb, NextPoint and Quanterix. Deutch, Taube and Cottrell hold a patent for a system and method for using machine learning on pathology slides to predict patient outcomes. Cimino-Mathews has received research grant funding from Bristol Myers Squibb. Seethala reports serving as an advisory board member for Astra Zeneca, BMS, Daichii Sankyo, Exact Sciences and Roche. Seethala receives research funding from BMS, Merck and Puma Biotechnology. Fiset has received honoraria, advisory and consultancy fees from Amgen, Astellas, AstraZeneca, EMD Serono, Hoffmann La Roche, Incyte, Merck, Novartis, Pfizer and Ventana. He has also received research funding from Astellas, AstraZeneca, Merck, Bristol Myers Squibb, Pfizer, Canadian Institute of Health Research/Cancer Research Society, Montreal General Hospital Foundation and the Rossy Cancer Network. Sholl receives research funding and consulting income from Genentech, has received research funding from Bristol Myers Squibb and is an advisory board member for Lilly. Scolyer has received fees for professional services from SkylineDx BV, IO Biotech ApS, MetaOptima Technology Inc., F. Hoffmann-La Roche Ltd, Evaxion, Provectus Biopharmaceuticals Australia, Qbiotics, Novartis, Merck Sharp & Dohme, NeraCare, AMGEN Inc., Bristol Myers Squibb, Myriad Genetics and GlaxoSmithKline. Signoretti receives commercial research grants from Bristol Myers Squibb, AstraZeneca, Exelixis, Merck, NiKang Therapeutics and Arsenal Biosciences; is a consultant/advisory board member for Merck, AstraZeneca, Bristol Myers Squibb, NextPoint Therapeutics, AACR and NCI; receives royalties from Biogenex; and mentored several non-U.S. citizens on research projects with potential funding (in part) from non-U.S. sources/foreign components. Tetzlaff has consultancy/advisory board relationships with Regeneron and Philogen, has performed central pathology review for Merck (money paid to UCSF) and Philogen (ongoing), and receives royalties from Elsevier. Ziai reports salary and employment with Genentech. The terms of all these arrangements are being managed by The Johns Hopkins University in accordance with its conflict-of-interest policies.
