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Personalizing Precision Oncology: From Light Microscope to Molecular Microscope.

The paradigm of cancer therapy is evolving from nonspecific cytotoxic drug therapy based on histologic diagnosis alone to one that aims to deliver the “right drug to the right patient at the right time.”1 With the advent of precision oncology fueled by clinical next-generation sequencing (NGS) has come an exponential growth in the use of genomically targeted therapy and immunotherapy. NGS is most commonly used in advanced, metastatic cancer and in rare cancers in which conventional histologic diagnosis may be challenging and for which there are few defined standard of care therapies. Because every patient’s sequence is unique, a precise molecular diagnosis and a customized treatment plan are needed when standard therapies become ineffective. Clinical NGS makes this feasible by enabling pathologists to supplement the histologic diagnosis with molecular data that, in turn, help clinicians develop a rational therapeutic strategy. For example, identifying a particular genomic aberration can open up new avenues of therapy, such as enrollment in a tissue-agnostic basket trial. When clinical trials are not an option, a therapy targeting a specific alteration may be used off-label if the treatment is approved in another tumor type for the same alteration. The decision tree for matched therapies outside clinical trials is often challenging, and the benefits versus risks of treatment need to be carefully weighed. In this issue of JNCCN, Tsai et al2 report an interesting case of metastatic undifferentiated carcinoma with clear cell change harboring multiple mutations, including a PTCH1 A925fs*6, W948* mutation refractory to hedgehog inhibition. This patient was successfully treated using immune checkpoint blockade therapy based on a commercially available comprehensive genomic panel. This case highlights several issues related to the contemporary, multidisciplinary management of cancer from diagnosis to therapy. One of the major challenges with respect to rare cancers or rare variants of common cancers is arriving at the correct pathological diagnosis. The diagnosis and classification of cancer have traditionally been rendered by pathologists who interpret the cytologic and architectural patterns of cells and stroma from microscopic examination of tissue sections stained by hematoxylin and eosin. Overlapping histologic features sometimes generate a differential diagnosis—in the report by Tsai et al, a clear cell neoplasm that could have been diagnosed as squamous cell carcinoma, basal cell carcinoma (BCC), or adnexal clear cell carcinoma—that may require clinical correlation and ancillary studies to resolve. Standard immunohistochemical studies may also be of limited utility, as in this case. NGS in this setting serves as a molecular microscope, enabling pathologists to reach a molecular diagnosis that can augment the histologic diagnosis. Also, the addition of genomic profiling to management of rare cancers adds a potential line of therapy for cancers that have little or no standard of care.3,4 In the report by Tsai et al,2 the sequencing results that showed multiple mutations, including a PTCH1 mutation, were a key feature in identifying the tumor as a BCC of variant histologic subtype. Without a precise diagnosis, a treatment plan is difficult to formulate. The diagnosis of BCC with a PTCH1 mutation helped