Understanding patterns of pathologic response following neoadjuvant immunotherapy for solid tumors
Authors: L.M. Sholl
Journal: Annals of Oncology (2018)

The widespread use of immunotherapeutics in oncology [immune-oncology (IO)] today represents a fundamental shift in the clinical approach to elimination of cancer cells. In contrast to the directly cytotoxic and/or cytostatic effects of conventional chemotherapy, radiotherapy, and targeted therapies, drugs directed at immune checkpoints, including PD-1/PD-L1 and CTLA4, harness the patient's immune system to effect tumor cell killing [1.Chen D.S. Mellman I. Elements of cancer immunity and the cancer-immune set point.Nature. 2017; 541: 321-330Crossref PubMed Scopus (2579) Google Scholar]. IO approaches have shown particular promise in solid tumors with a high burden of immunogenic neoantigens, such as non-small-cell lung cancer (NSCLC) and melanoma, and currently represent standard of care treatment of at least a subset of patients with these tumor types [2.Taube J.M. Galon J. Sholl L.M. et al.Implications of the tumor immune microenvironment for staging and therapeutics.Mod Pathol. 2018; 31: 214-234Crossref PubMed Scopus (206) Google Scholar]. Radiographic studies of tumors undergoing immunotherapy have identified some distinctive patterns of tumor response, such as pseudoprogression and development of new lesions despite shrinking of the baseline tumor, triggering proposals for revised approaches to radiographic response evaluation in IO-treated patients [3.Nishino M. Dahlberg S.E. Adeni A.E. et al.Tumor response dynamics of advanced non-small cell lung cancer patients treated with PD-1 inhibitors: imaging markers for treatment outcome.Clin Cancer Res. 2017; 23: 5737-5744Crossref PubMed Scopus (55) Google Scholar, 4.Hodi F.S. Ballinger M. Lyons B. et al.Immune-modified response evaluation criteria in solid tumors (imRECIST): refining guidelines to assess the clinical benefit of cancer immunotherapy.J Clin Oncol. 2018; 36: 850-858Crossref PubMed Scopus (206) Google Scholar]. These unique radiographic patterns are thought to represent tumor infiltration by immune cells, however, the actual reasons for dynamic changes in radiographic tumor appearance can only be inferred from imaging studies. A recently published neoadjuvant trial of PD-1 blockade (nivolumab) in NSCLC followed by definitive surgical resection yielded promising results in terms of tumor response and provided an opportunity to study the cellular components of tumors exposed to immune checkpoint blockade [5.Forde P.M. Chaft J.E. Smith K.N. et al.Neoadjuvant PD-1 blockade in resectable lung cancer.N Engl J Med. 2018; 378: 1976-1986Crossref PubMed Scopus (1027) Google Scholar]. Data generated in this trial, as well as preliminary data from studies of neoadjuvant PD-1 and/or CTLA4 inhibition in melanoma [6.Rozeman E.A. Blank C.U. Akkooi A.C. et al.Neoadjuvant ipilimumab + nivolumab (IPI+NIVO) in palpable stage III melanoma: updated data from the OpACIN trial and first immunological analyses.J Clin Oncol. 2017; 35: 9586Crossref Google Scholar, 7.Huang A.C. Orlowski R.J. George S.M. et al.Safety, activity, and biomarkers for neoadjuvant anti-PD-1 therapy in melanoma. American Association for Cancer Research, Chicago, IL2018Google Scholar] have identified some unique histologic features of the tumor bed following immune checkpoint blockade. In this issue of Annals of Oncology, Cottrell et al. [8.Cottrell T.R. Thompson E.D. Forde P.M. et al.Pathologic features of response to neoadjuvant anti-PD-1 in resected non-small-cell lung carcinoma: a proposal for quantitative immune-related pathologic response criteria (irPRC).Ann Oncol. 2018; 29: 1853-1860Abstract Full Text Full Text PDF PubMed Scopus (201) Google Scholar] report on their systematic pathologic analysis of the 20 cases of NSCLC resected in the neoadjuvant nivolumab trial. The authors highlight several features that distinguish pathologic responders from non-responders following PD-1 blockade, including fibrosis, neovascularization, cholesterol clefts, high numbers of tumor infiltrating lymphocytes (TILs), and tertiary lymphoid structures. Notably, only 10% of patients in the trial showed a radiographic partial response and none showed complete response, which contrasted with a 45% major pathologic response (mPR) rate (following definitions established for conventional chemotherapy—described below), including three patients with complete pathologic response (cPR) in the primary tumor bed [5.Forde P.M. Chaft J.E. Smith K.N. et al.Neoadjuvant PD-1 blockade in resectable lung cancer.N Engl J Med. 2018; 378: 1976-1986Crossref PubMed Scopus (1027) Google Scholar, 8.Cottrell T.R. Thompson E.D. Forde P.M. et al.Pathologic features of response to neoadjuvant anti-PD-1 in resected non-small-cell lung carcinoma: a proposal for quantitative immune-related pathologic response criteria (irPRC).Ann Oncol. 2018; 29: 1853-1860Abstract Full Text Full Text PDF PubMed Scopus (201) Google Scholar]. This discrepancy can be explained by the presence of stromal tissue and immune cells replacing the tumor mass—a phenomenon termed 'regression bed'—so that the radiographic and gross mass volume are concordant, whereas viable tumor comprises at most a small percentage of the mass in patients with mPR. In comparison to historic observations of neoadjuvant cytotoxic therapy, where hyalinized fibrosis and coagulation necrosis tend to predominate in treated tumors, pathologic response patterns following PD-1 blockade appear to reflect a state of immune activation (Figure 1) [1.Chen D.S. Mellman I. Elements of cancer immunity and the cancer-immune set point.Nature. 2017; 541: 321-330Crossref PubMed Scopus (2579) Google Scholar, 8.Cottrell T.R. Thompson E.D. Forde P.M. et al.Pathologic features of response to neoadjuvant anti-PD-1 in resected non-small-cell lung carcinoma: a proposal for quantitative immune-related pathologic response criteria (irPRC).Ann Oncol. 2018; 29: 1853-1860Abstract Full Text Full Text PDF PubMed Scopus (201) Google Scholar]. The relative insensitivity of computed tomography for documenting response in the neoadjuvant setting highlights the importance of pathology in response assessment following definitive surgery. This, of course, prompts then need for standardized methods of gross and microscopic evaluation to ensure adequate sampling and reproducible response scoring. To date, few systems of pathologic neoadjuvant response assessment have been consistently shown to significantly predict outcomes. The breast cancer field is considered to have the gold standard for pathologic response assessment following neoadjuvant therapy; however, even here there are no fewer than eight proposed models of gross and histologic assessment, only some of which significantly predict outcomes and then only in a subset of cancer subtypes [9.von Minckwitz G. Untch M. Blohmer J.U. et al.Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes.J Clin Oncol. 2012; 30: 1796-1804Crossref PubMed Scopus (1711) Google Scholar, 10.Corben A.D. Abi-Raad R. Popa I. et al.Pathologic response and long-term follow-up in breast cancer patients treated with neoadjuvant chemotherapy: a comparison between classifications and their practical application.Arch Pathol Lab Med. 2013; 137: 1074-1082Crossref PubMed Scopus (45) Google Scholar]. In the lung, cPR is associated with improved survival in patients with stage I-III NSCLC; cPR, however, is observed on average in only 4% of patients in neoadjuvant chemotherapy trials [11.Hellmann M.D. Chaft J.E. William W.N. et al.Pathological response after neoadjuvant chemotherapy in resectable non-small-cell lung cancers: proposal for the use of major pathological response as a surrogate endpoint.Lancet Oncol. 2014; 15: e42Abstract Full Text Full Text PDF PubMed Scopus (285) Google Scholar]. In 1997, Junker et al. [12.Junker K. Thomas M. Schulmann K. et al.Tumour regression in non-small-cell lung cancer following neoadjuvant therapy. Histological assessment.J Cancer Res Clin Oncol. 1997; 123: 469-477Crossref PubMed Scopus (132) Google Scholar] proposed that 10% or less residual viable tumor based on extensive sampling (up to 58 blocks of tissue submitted per tumor in their study) represented a clinically relevant cut point in stage IIIA/B tumors, associated with a significant improvement in overall survival (27.9 versus 13.7 months for nonresponders). Although this cut point has not predicted outcomes in all subsequent analyses, likely due to confounding effects of radiation therapy in some studies, the burden of evidence suggests that 10% or less residual viable tumor is a reasonable surrogate for overall survival in neoadjuvant-treated NSCLC and thus serves as the definition for mPR [11.Hellmann M.D. Chaft J.E. William W.N. et al.Pathological response after neoadjuvant chemotherapy in resectable non-small-cell lung cancers: proposal for the use of major pathological response as a surrogate endpoint.Lancet Oncol. 2014; 15: e42Abstract Full Text Full Text PDF PubMed Scopus (285) Google Scholar]. Nodal downstaging and clearance also appears to be a robust predictor of overall survival following neoadjuvant chemoradiotherapy [11.Hellmann M.D. Chaft J.E. William W.N. et al.Pathological response after neoadjuvant chemotherapy in resectable non-small-cell lung cancers: proposal for the use of major pathological response as a surrogate endpoint.Lancet Oncol. 2014; 15: e42Abstract Full Text Full Text PDF PubMed Scopus (285) Google Scholar]. Nodal assessment is confounded, however, by both surgical and pathologic sampling [13.David E.A. Cooke D.T. Chen Y. et al.Does lymph node count influence survival in surgically resected non-small cell lung cancer?.Ann Thorac Surg. 2017; 103: 226-235Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar, 14.Smeltzer M.P. Faris N. Yu X. et al.Missed intrapulmonary lymph node metastasis and survival after resection of non-small cell lung cancer.Ann Thorac Surg. 2016; 102: 448-453Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar]. Acknowledging these benchmarks, but also recognizing the distinct mechanisms of tumor killing associated with IO, studies of outcomes based on pathologic response assessment following neoadjuvant therapy will be required and the definition of mPR that best predicts survival will need to be established. Cottrell et al., as well as Tetzlaff et al. [15.Tetzlaff M.T. Messina J.L. Stein J.E. et al.Pathological assessment of resection specimens after neoadjuvant therapy for metastatic melanoma.Ann Oncol. 2018; 29: 1861-1868Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar] in this same issue, begin to lay the groundwork for the re-examination of pathologic response assessment following neoadjuvant IO for NSCLC and melanoma, respectively. With a detailed description of response patterns following PD-1 therapy now in hand, the next steps for the pathology community should include: (i) confirming that the observed patterns hold across mechanistically distinct forms of IO; (ii) establishing optimal sampling for accurate response classification; (iii) applying digital imaging to provide a more rigorous approach to response quantitation; and (iv) examining the role for a more nuanced evaluation of the immune cell milieu, including through use of multiplex immune profiling, to understand the interactions that promote or suppress response to these agents in the neoadjuvant setting. Standardization of practice is, as always, of critical importance for reproducibility and accurate outcomes prediction. Notably, Cottrell et al. demonstrate that the reproducibility of their proposed immune-related pathologic response criteria is superior to that of conventional neoadjuvant chemotherapy scoring systems, however, larger studies will be required to confirm the performance of these criteria. Finally, consistent documentation of response patterns relevant to IO, codified by a synoptic reporting structure, should be informed by ongoing trials and implemented in practice. None declared.