Rare Cancers and Complex Cancer cases treatments

Rare cancers and “complex” oncology cases, treatment is often driven by expert pathology and multidisciplinary review, molecular profiling when it can change therapy, and prioritizing clinical trials when standard options are limited.

Multidisciplinary evaluation and referral

Because many rare tumors require multimodality care and nuanced surgical and radiation decisions, evaluation and management are ideally done in centers with disease-specific expertise and a multidisciplinary team.

Molecular profiling and “tumor-agnostic” treatment opportunities

Biomarker-driven therapy is increasingly important in advanced refractory cancers, and multigene panel-based tumor testing can identify actionable alterations. Given tissue-agnostic approvals (eg, high tumor mutational burden, mismatch repair deficiency, NTRK fusions, RET fusions), this provides a rationale for broad testing across solid tumors when a patient would be a candidate for these treatments.

When a clinical trial is available, off-label or off-study use of targeted therapies approved for other diseases is not recommended without evidence of meaningful efficacy.

Cancer of unknown primary as a common “complex case” pattern

If an anatomic primary site is identified, the patient should no longer be classified as cancer of unknown primary (CUP), and treatment should follow standard guidelines for the identified tumor type.

A substantial subset of CUP can be assigned to clinicopathologic subsets where specific therapy is useful, and many others can receive site-specific therapy based on immunohistochemistry and/or molecular cancer classifier assays. For patients not in a specific subset, standard management can integrate site-specific therapy (based on immunohistochemistry and/or molecular cancer classifier assays) plus molecularly guided therapy based on comprehensive molecular profiling, with empiric chemotherapy reserved for those without a predicted site of origin and without targetable alterations.

Sarcoma as another “complex case” pattern

For metastatic soft tissue sarcoma without a specific histologic diagnosis, diagnostic assays that can identify mutations and gene fusions or translocations are obtained, guided by a pathologist with sarcoma expertise. Next-generation sequencing is not routinely obtained in all metastatic soft tissue sarcoma prior to initiating therapy because the yield of actionable mutations is very low in most sarcomas, and its role is not established.

Examples of rare cancers by category

• Breast cancers with rare histologies: tubular, mucinous, micropapillary, metaplastic, neuroendocrine, adenoid cystic, secretory, and apocrine carcinoma.

• Rare subtypes of metaplastic breast carcinoma with favorable prognosis include low-grade adenosquamous and low-grade fibromatosis-like carcinoma.

• Rare endometrial carcinoma subtypes include mesonephric and mesonephric-like adenocarcinoma, gastric type mucinous carcinoma, and pure squamous cell carcinoma of the endometrium.

Rare primary tumor sites

• Small bowel adenocarcinoma (a primary small bowel malignancy).

• Cancer of unknown primary (CUP) is a distinct clinical entity (metastatic cancer where an anatomic primary site is not identified after appropriate evaluation).

Rare tumor families

• Head and neck sarcomas are rare (approximately 2 percent of head and neck malignancies).

• Uncommon brain tumors comprise many distinct entities beyond diffuse gliomas, meningiomas, and metastases.

• Rare primary cutaneous T cell lymphoma subtypes are extremely rare and heterogeneous.

Rare cancers enriched for specific gene fusions

• Rare cancers with a high frequency of NTRK fusions include infantile fibrosarcoma, congenital mesoblastic nephroma (cellular subtype), secretory breast carcinoma, and secretory carcinoma of the salivary gland.