Functional Precision Medicine Successfully Guides Therapeutic Regimen of 'Cancer of Unknown Primary' Later Classified as Triple-Negative Breast Cancer: A Case Report.

Introduction: Controlled randomized trials, molecular analytics, and guideline recommendations have so far been irreplaceable tools to ensure appropriate treatment and decision-making for physicians and patients. Individual patient models are increasingly complementing these methods, particularly in the case of advanced cancers, rare cancers, and cancers of unknown primary (CUP), as in these cases comprehensive clinical evidence is unavailable, often resulting in poor treatment success, even after stratification. Case Presentation: Here we report a 53-year-old patient with CUP with axillary lymph node metastases for whom patient-derived 3D (PD3D®) tumor organoids successfully guided personalized treatment. PD3D tumor models were used to screen drugs that are effective at the suspected primary tumor site. The screen revealed sensitivity to doxorubicin, which is not indicated for CUP treatment but hinted toward breast cancer that was subsequently confirmed as triple-negative breast cancer (TNBC). The patient showed partial remission to first-line doxorubicin and cyclophosphamide, which were followed by docetaxel. Subsequent radiotherapy eventually led to a complete remission, which is still ongoing. Conclusion: We conclude that pre-therapeutic drug sensitivity screening with PD3D tumor models can be essential in guiding and enabling an effective personalized treatment for patients with hard-to-treat cancers, like CUP or TNBC.

Photon and Proton irradiation in Patient-derived, Three-Dimensional Soft Tissue Sarcoma Models.

BACKGROUND: Despite their heterogeneity, the current standard preoperative radiotherapy regimen for localized high-grade soft tissue sarcoma (STS) follows a one fits all approach for all STS subtypes. Sarcoma patient-derived three-dimensional cell culture models represent an innovative tool to overcome challenges in clinical research enabling reproducible subtype-specific research on STS. In this pilot study, we present our methodology and preliminary results using STS patient-derived 3D cell cultures that were exposed to different doses of photon and proton radiation. Our aim was: (i) to establish a reproducible method for irradiation of STS patient-derived 3D cell cultures and (ii) to explore the differences in tumor cell viability of two different STS subtypes exposed to increasing doses of photon and proton radiation at different time points. METHODS: Two patient-derived cell cultures of untreated localized high-grade STS (an undifferentiated pleomorphic sarcoma (UPS) and a pleomorphic liposarcoma (PLS)) were exposed to a single fraction of photon or proton irradiation using doses of 0 Gy (sham irradiation), 2 Gy, 4 Gy, 8 Gy and 16 Gy. Cell viability was measured and compared to sham irradiation at two different time points (four and eight days after irradiation). RESULTS: The proportion of viable tumor cells four days after photon irradiation for UPS vs. PLS were significantly different with 85% vs. 65% (4 Gy), 80% vs. 50% (8 Gy) and 70% vs. 35% (16 Gy). Proton irradiation led to similar diverging viability curves between UPS vs. PLS four days after irradiation with 90% vs. 75% (4 Gy), 85% vs. 45% (8 Gy) and 80% vs. 35% (16 Gy). Photon and proton radiation displayed only minor differences in cell-killing properties within each cell culture (UPS and PLS). The cell-killing effect of radiation sustained at eight days after irradiation in both cell cultures. CONCLUSIONS: Pronounced differences in radiosensitivity are evident among UPS and PLS 3D patient-derived sarcoma cell cultures which may reflect the clinical heterogeneity. Photon and proton radiation showed similar dose-dependent cell-killing effectiveness in both 3D cell cultures. Patient-derived 3D STS cell cultures may represent a valuable tool to enable translational studies towards individualized subtype-specific radiotherapy in patients with STS.

Precision Oncology Beyond Genomics: The Future Is Here-It Is Just Not Evenly Distributed.

Cancer is a multifactorial disease with increasing incidence. There are more than 100 different cancer types, defined by location, cell of origin, and genomic alterations that influence oncogenesis and therapeutic response. This heterogeneity between tumors of different patients and also the heterogeneity within the same patient's tumor pose an enormous challenge to cancer treatment. In this review, we explore tumor heterogeneity on the longitudinal and the latitudinal axis, reviewing current and future approaches to study this heterogeneity and their potential to support oncologists in tailoring a patient's treatment regimen. We highlight how the ideal of precision oncology is reaching far beyond the knowledge of genetic variants to inform clinical practice and discuss the technologies and strategies already available to improve our understanding and management of heterogeneity in cancer treatment. We will focus on integrating multi-omics technologies with suitable in vitro models and their proficiency in mimicking endogenous tumor heterogeneity.