Molecular diagnostics and therapies for gastrointestinal tumors: a real-world experience

In gastrointestinal (GI) oncology, genetic alterations can serve both as negative, as well as positive predictive biomarkers. For instance, since the concept that KRAS mutant colorectal cancer patients do not benefit from the addition of EGFR antibodies to the chemotherapy backbone was introduced, determination of RAS status has become part of the routine diagnostic workup in patients with advanced colorectal cancer (Di Fiore et al. 2007; Karapetis et al. 2008). In contrast, while there is accumulating evidence that microsatellite instable (MSI) GI cancers do not derive significant benefit from perioperative chemotherapy, several studies confirmed a strong positive correlation between MSI high status and response to immunotherapies (Andre et al. 2020; Le et al. 2017b; Pietrantonio et al. 2019; Seymour and Morton 2019; Smyth et al. 2017). Genetic alterations can also create distinct vulnerabilities and serve as targets for precision oncology approaches. With an expanding repertoire of targeted agents and clinical data on precision oncology in solid tumors, molecular diagnostics using high-throughput sequencing technologies are becoming increasingly important and are integrated in routine clinical diagnostics. Especially in higher lines of therapy and in malignancies with limited therapeutic options, panel sequencing can identify molecular targets for therapy and help to ensure, that the full spectrum of clinically meaningful treatment options is offered to patients. However, access to targeted drugs is often hampered by the lack of approval by the European authorities, namely the European Medicines Agency (EMA), and without this approval, treating physicians need to file for cost coverage by the health insurance companies on an individual basis.

In the following, we report our experiences with molecular diagnostics in GI malignancies, outline the formal requirements and temporal processes associated with approval of cost coverage by German health insurance companies, and assess the clinical response we observed in patients that received individualized therapies in our center.

The clinical relevance of precision oncology is increasingly recognized for solid malignancies, including gastrointestinal cancers. Targeted treatments can extend the therapeutic spectrum on an individual patient’s basis and, in some cases, have the potential to significantly alter the clinical course of the disease. Treatment-relevant genetic alterations are frequently diagnosed by panel sequencing. To ensure that efficient therapies are not withheld from the patients, it is critical to choose molecular diagnostics that are capable of detecting all therapeutically relevant genetic alterations.

The selection of a panel is often heavily biased by the diagnostic procedures that are established at the local molecular pathology, and may represent a compromise between cost-effectiveness and diagnostic depth. Some focused panels are customized for specific tumor entities, and may therefore fail to provide sufficiently comprehensive information if applied to other cancers. The importance of matching the panel diagnostics to the genetic landscape of the individual entities is exemplified by biliary tract cancers: while FGFR2 fusions are nearly absent in extrahepatic cholangiocarcinomas, they occur with a high frequency (10–15%) in patients with intrahepatic cholangiocarcinoma (Lamarca et al. 2020). Therefore, although a specific panel might be well suited for diagnostic workup in tumors that arise from the extrahepatic bile ducts, it might fail to detect critical alterations of the intrahepatic counterparts.

An additional and important caveat, which can be easily overlooked by the treating physicians, is, that even if the panel lists specific gene names, not all platforms necessarily cover the entirety of relevant alterations. As an example, a post hoc analysis of a recent clinical trial (FIGHT-202) revealed that only 50% of the detected FGFR2 fusions had been described before (Abou-Alfa et al. 2020b; Silverman et al. 2021). Based on the hybrid capture technology of the Foundation One CDx assay that was used as companion diagnostics within the FIGHT-202 trial, chromosomal FGFR2 rearrangements could be detected without prior knowledge of the partner gene, whereas amplicon-based panels would have failed to detect rearrangements for which specific partner gene primers were missing from the sequencing reaction. The Oncomine Comprehensive Cancer panel v3, for instance, currently only detects 25 different FGFR2 fusions from the > 150 FGFR fusion documented to date. In line with this disparity, we identified FGFR2 fusions in two out of nine patients from our local cohort which had not been detected by the amplicon approach.

Ideally, however, repetitive rounds of sequencing diagnostics should be avoided by choosing the most suitable testing strategies to circumvent unnecessary cost and time loss. To match patients with optimized molecular tests, a close interaction between molecular pathology and the clinical care providers is crucial, and we advocate that these diagnostics should be best performed in centralized referral centers. Traditionally, pathologists were primarily involved in the initial organ-specific classification of the malignant disease. Now, the molecular pathologist is becoming more visible in daily clinical practice, as informed clinical decision making warrants the careful evaluation and interpretation of sequencing results. The importance of this interaction is reflected by the growing number of molecular tumor boards (Hoefflin et al. 2021).

Finally, standardized “tracking” systems for tissues shipped from external pathologies are lacking, and uncertainty concerning the whereabouts of the materials that are needed for panel sequencing can further complicate the diagnostic processes and prolong treatment initiation. Together, this leads to an unacceptable number of patients that deteriorate prior to initiation of targeted therapies.

Our single-center experience illustrates that the integration of precision medicine in clinical treatment concepts continues to be a challenge in GI oncology in Germany: Especially in “rare” malignancies such as cancers of the biliary system, the individual genetically defined subgroups are small, which often hampers patient accrual for precision oncology trials. Positive data from phase III trials, however, are commonly expected before targeted agents gain approval by the European Medical Agency. Prior to EMA approval, physicians are usually required to file for cost coverage by the insurance providers based on the individual clinical records, which can be a time-consuming process. In some cases, the timeframe until a response was issued by the German insurance providers exceeded 5 weeks. Furthermore, the experience of our real-world cohort shows that the reasons for denial of coverage are often not based on a lack of evidence. In multiple cases, applications were rejected despite a high level of evidence (ESCAT IA). Early access/compassionate use programs can fill the gap between clinically meaningful data and EMA approval. In the absence of suitable clinical trials, the possibility to include patients into these programs should be explored.

In our analysis, the comparison of progression-free survival favored the personalized therapy approach, and we observed a significant increase in the progression-free survival under molecular therapy compared to the immediate prior therapy in those patients that initially responded to the personalized approach. To further optimize outcome, and avoid toxicity as well as unnecessary cost of targeted drugs, molecular as well as clinical “biomarkers”, such as optimal timing of response assessment, should be evaluated consistently and assessed for their suitability as early predictors of treatment efficacy. Of note, patients were frequently referred to our center at advanced disease stages, and after several lines of therapy. Therefore, it is well conceivable, that the efficiency of precision oncology in real-world cohorts from GI cancer patients do not meet the responses reported from clinical trials. Especially in cancers with a limited number of effective or approved treatments available, such as cholangiocarcinoma, we strongly advocate the early implementation of molecular diagnostics, even though insurance agencies in Germany usually grant cost coverage for individualized approaches only after exhaustion of standard treatments. This early testing strategy is also endorsed by recommendations published by the European Society of Medical Oncology (ESMO) (Mosele et al. 2020).

In summary, we believe that the potential of precision medicine in GI cancers is not yet being fully exploited in Germany and that the hurdles that need to be taken into account before a patient receives a molecular therapy are substantial and time consuming.

More precise guidelines on the initiation of NGS diagnostics, and routine referral to reference centers with ample experience in the contextual interpretation of and reaction to molecular results, would likely be beneficial in the implementation of precision oncology in Germany.