BioT3 Integrates Diagnosis With Actionable Biomarkers in Metastatic Cancer

Metastatic disease accounts for the vast majority of cancer-related deaths. Ensuring a definitive diagnosis and the most effective treatment in a timely fashion is essential for extending life expectancy.¹Despite a spurt in knowledge regarding treatment-related biomarkers and availability of the latest technologies to probe these in an efficient manner, the uptake of these technologies in community practice has been highly suboptimal. In some cases, this lag can create a perception that community practices are not “keeping up” relative to academic centers with respect to the use of these latest technologies.

Ralph Boccia, MD, FACP, is medical director of the Center for Cancer and Blood Disorders and clinical associate professor of medicine at Georgetown University, as well as a consulting medical director of the International Oncology Network clinical program and chairman of their medical advisory panel. He has been involved in assessing the clinical value of some of these technologies and agrees that the use of genomics beyond the usual breast and lung cancer assays has had slow uptake in general practice in large part because universal, broadbased understanding of how best to use these tools is lacking.

The Challenge of Accurate Diagnosis in Metastatic Disease

With a clear need for more practice-friendly solutions, the ultimate goal is to integrate accurate diagnosis with comprehensive biomarker information to achieve precision therapy that reflects the heterogeneity of the disease. A San Diego-based company has created a suite of genomic-based tests called bioT3 that aims to provide community oncologists with the tools to achieve these goals, while being conscious of high actionability, low tissue use, cost and turn-around time.Identification of a single confirmed diagnosis of tumor type and subtype and of the most effective therapeutic options for metastatic disease are critical aspects for ensuring optimal treatment and extending life expectancy. Typically, a diagnosis is made using standard pathologic techniques: examining the morphology of the cancer cells and performing immunohistochemical (IHC) analyses to identify specific cellular markers. However, there is frequent ambiguity in the diagnosis of metastatic cancer; each year in the United States, as many as 90,000 to 130,000 newly diagnosed metastatic patients have unclear diagnoses, about 25% to 40% of which are classified as cancer of unknown primary (CUP).^2-5IHC, which is the current standard of care for tumor classification has been shown to be accurate in only ~2 out of 3 metastatic cases,^3-4consistent with older studies which also point to similar challenges related to achieving an accurate diagnosis.⁶

More recently, a recent study at MD Anderson⁷shed light on the problem of diagnostic ambiguity. A total of 2714 cancer cases were reexamined by an expert pathologist. In a surprisingly high number of cases (25%), the diagnosis was changed upon the expert review. In recent years, molecular tumor classification has emerged as an important technique in tumor diagnostics that is proving to be effective in identifying tumor type. By providing a more accurate diagnoses, molecular classification can be used to help a physician choose the most effective treatment, particularly in the context of targeted therapy. Conversely, lack of a definitive diagnosis limits potential therapeutic options. F. Anthony Greco, MD, director of the Sarah Cannon Cancer Center in Nashville, Tennessee explained, “Understanding where a tumor is coming from is extremely important [because] we treat cancers based on their site of origin. Once you feel confident with what type of cancer the patient has, there are a number of other molecular tests that are now standard.”

Recently, there has been debate in the academic community on the taxonomy of cancers,⁸with some in the industry arguing for the use of sequencing alone to treat patients with unclear diagnosis.⁹Cohen and Settleman wrote a comprehensive review,¹⁰which put the debate into a practical clinical context. The authors (from Genentech and Calico) explain that use of driver mutation alone to treat patients is inconsistent with clinical evidence to-date. Firstly, most clinical trials have inclusion criteria that are cancer specific. Secondly, there are a variety of examples that show that targeted therapies linked to specific biomarkers show different responses depending on the cancer type. For example:

• Vemurafenib is effective in patients with melanoma who have BRAF V600E mutations, while clinical study data did not show significant efficacy in colorectal cancer patients with the same mutation.
• Overexpression of the human epidermal growth factor receptor 2 (HER2) is indicative of trastuzumab efficacy in breast cancer and gastric cancer, but not in non-small cell lung cancer (NSCLC).
• Cetuximab is approved for patients with colorectal cancer who have wild-type KRAS mutational status, while clinical study data show that patients with advanced biliary tract cancer who have the same wildtype KRAS status do not benefit.
• Tamoxifen is an established and effective therapy for patients with estrogen receptor-positive (ER+) breast cancer, but is not effective in patients with ER+ melanoma. Finally, without a single confirmed diagnosis, ease of access to and reimbursement of targeted agents can be problematic. Thus, with the ever-expanding list of targeted biomarker-driven agents tied to specific cancer types, accurate diagnosis is now more important than ever before.

Boccia agrees that biomarker information alone is unhelpful and may in fact hinder clinical decision making. He outlined the importance of genomic profiling technologies in this endeavor, “When you offer people the profile that may show multiple abnormalities, it leaves them floundering with what to do with that information,” he said. Boccia believes that BioT3 offers community practice doctors a valuable service by combining diagnosis and biomarker analysis in a single platform. “We treat patients based on the tumor type or cellular context of the tumor rather than the sites of metastases, and simply knowing what biomarkers are present is not always helpful.” Citing the example of BRAF mutations, he stressed that in these cases, it is critical to distinguish the primary tumor type.

CancerTYPE ID

“We can now rely on some of these assays, with bioTheranostics being one of the sources using assays like BioT3, to help us do that, to better predict where tumors are coming from in patients in whom the presenting picture is not clear, so we can better initiate therapy based on that indication and interpretation.”CancerTYPE ID from bioTheranostics in San Diego is the most commonly used gene expression— based tumor-classification assay. It identifies the type and subtype of a tumor by performing a realtime RT-PCR assay of 92 genes on formalin-fixed paraffin-embedded tissue biopsies. The resulting 92-gene expression profile can help diagnose 28 tumor types and 50 subtypes.¹¹Boccia discussed the importance of improved diagnostic tools in the metastatic setting. “Cancer-Type ID helps us more accurately identify the tumor type in a patient with advanced cancer when not obvious or apparent, or in situations where the presentation is unusual and the diagnosis or primary site is questionable.”

Greco and other researchers at the Sarah Cannon Research Institute are among those who have been involved in the clinical evaluation of this assay. “It’s quite reliable in identifying the tissue of origin or the cancer type in patients with unclear diagnosis,” Greco said. Important clinical studies that validated the platform include:

• A large, blinded, multi-institutional study across Massachusetts General, Mayo and UCLA, CancerTYPE ID, which demonstrated 87% accuracy in identifying the 28 main tumor types and 82% accuracy for the 50 subtypes, with consistently high accuracy across several clinically relevant subsets (eg, cases with extremely limited tissue based on FNA)¹²
• A prospective trial of 252 patients with CUP, in which CancerTYPE ID was able to identify a single diagnosis of tumor type in 98% of patients, showed a 37% improvement in OS relative to historical controls, and identified 60% of patients who had tumors that were more responsive to site-directed therapy¹³
• A blinded comparator study of 122 patients with difficult to diagnose, poorly differentiated or undifferentiated tumors, in which CancerTYPE ID showed statistically higher accuracy overall versus IHC, the current standard of care for diagnosis of tumor type⁴

“When you put it together with clinical examination and standard pathology and other specialized pathology tests, in the majority of patients we can now tell where the cancer’s coming from; then, we can treat according to the type of cancer they have rather than just using this sort of shotgun therapy as we’ve been doing for 30 years, so-called empiric chemotherapy,” Greco said.

CancerTREATMENT NGS+

Studies have also demonstrated the clinical utility of CancerTYPE ID. Interim results from a 28-site registry study, involving 134 patients, showed that its use changed the treatment decision in more than half of cases.¹⁴Further, a physician-reported clinical utility study¹⁵found that CancerTYPE ID identified a primary tumor type not previously considered in one-fourth of all patients. The test has been widely used across the US with more than 22,000 tumor samples analyzed to-date and is covered by Medicare Part B reimbursement with no patient copay, and by an increasing number of commercial insurance companies.Once an accurate diagnosis has been established, an equally important step is to identify the mutational profile of a tumor. Because genetic alterations may be indicative of response or resistance to certain drugs, understanding the profile of a tumor is important to achieve optimal patient outcomes “We now know that there are certain genetic abnormalities that you can treat with drugs that are on the market and FDA-approved, and several others have prominent associated clinical trials,” explained Greco.

CancerTREATMENT NGS+ is designed to address 4 critical needs of the community oncologist that were inadequately addressed:

• Maximal actionability
• Low tissue use and rejection rates (“QNS”)
• Fast turn-around time
• Low cost

According to BioTheranostics, the company aims to address these needs through specific design aspects of their platform:

• Actionability is defined strictly based on either NCCN recommendations for prominent cancer types or major phase II/III clinical trials, which they state will allow the use of minimal tissue while keeping the turnaround time and cost low
• Use of a 50-gene Ion Torrent next-generation sequencing panel from Life Technologies, which offers high speed and coverage of the most actionable genes¹⁶
• A selected list of FISH and IHC tests that they believe will fill the key gaps in actionability, while keeping turnaround time, cost, and QNS low

Tumor-specific biomarker panels are offered for cancers with biomarker-driven FDA-approved treatment options, including NSCLC, CRC, breast cancer, and melanoma, while a more comprehensive panel is offered for all other cancers to identify potential driver mutations and clinical trials that a patient may be eligible to enter. Boccia explained that for these 5 cancer types, “We have very well-studied, documented and proven uses for some of these tools.” He continued, “There are relationships where you can associate mutations in certain pathways with certain drug behaviors and responses.” Clinicians can use these alterations to guide therapeutic decision-making. According to Boccia, “There’s no doubt that use of this profiling analysis among academic and community physicians can help us to plan therapies based on what we know about those biomarkers.”

Greco pointed out that numerous companies now offer next-generation sequencing of biopsy specimens and, while some companies such as Foundation Medicine use a sequencing approach alone, others like bioTheranostics take a more comprehensive approach by including both genetic mutation and protein expression (IHC). Boccia explained the benefits of this approach, “Besides sequencing, CTID provides, additionally, FISH and IHC testing, which further enhances high actionability of results; their information and reports are concise and offer these benefits.”

BioTheranostics believes addition of IHC tests, which measure the level of a specific protein’s expression, allows examination of new mechanisms relevant in melanoma and NSCLC such as PD-L1,^17,18as well as older biomarkers such as HER2, ER, and PR expression relevant in breast cancer. For patients with NSCLC, they perform ALK rearrangement testing with FISH (vs NGS), because this is consistent with the inclusion criteria of the crizotinib pivotal studies,¹⁹and the recent ASCO/IASLC guidelines.²⁰

By combining NGS with a specific list FISH/IHC tests, the company aims to achieve good turn-around times:

• 5-7 days for patients with clear diagnosis, which involves testing CancerTREATMENT NGS+ alone
• 7-10 days for patients with unclear diagnosis, which involves testing CancerTREATMENT NGS+ with CancerTYPE ID

“Extraordinarily important to practices is fast turn-around,” said Boccia. There is nothing worse than making patients wait long periods of time to get results that allow us to select and tailor the best therapies for patients rather than taking the old shotgun approach.”Greco stated that he considers the cost of obtaining these tests by bioTheranostics to be competitive. Boccia agreed and explained why he felt cost to be an important factor, “[bioTheranostics] cost is less than some of the other large labs currently offering biomarker analyses in a variety of ways; given rising health care costs in general, and payors sometimes challenging expensive testing, and given there are now new reimbursement models that have cost and risk sharing, cost becomes more and more important.”

In the past several decades, we have begun to capitalize on technological advances and a deeper understanding of the molecular heterogeneity of cancer to improve diagnosis and treatment. The creation of more practice-friendly solutions is an important step in ensuring wider use of these state-of-the-art technologies aimed at more optimal patient outcomes.

References

1. Sporn MB. The war on cancer.Lancet. 1996;347:1377-1381.
2. Fong TH, Govindan R, Morgensztern D. Cancer of unknown primary.J Clin Oncol. 2008;26(15 suppl):22159.
3. Anderson GG, Weiss LM. Determining tissue of origin for metastatic cancers: meta-analysis and literature review of immunohistochemistry performance.Appl Immunohistochem Mol Morphol. 2010;18(1):3-8.
4. Weiss LM, Chu P, Schroeder B, et al. Blinded comparator study of immunohistochemical analysis versus a 92-gene cancer classifier in the diagnosis of the primary site in metastatic tumors.J Mol Diagn. 2013;15(2):263-269.
5. Laouri M, Schroeder B, Chen E, Erlander G, Schnabel C. Diagnostic utility of molecular profiling for cancers of uncertain primary.J Clin Oncol. 2011;29(suppl). Abstract e21103.
6. Raab SS, Grzybicki DM, Janosky JE, et al. Clinical impact and frequency of anatomic pathology errors in cancer diagnoses.Cancer. 2005;104:2205- 2213.
7. Middleton LP, Feeley TW, Albright HW, Walters R, Hamilton SH. Secondopinion pathologic review is a patient safety mechanism that helps reduce error and decrease waste.J Oncol Pract. 2014;10(4):275-280.
8. Hoadley KA, Yau C, Wolf DM, et al. Multiplatform analysis of 12 cancer types reveals molecular classification within and across tissues of origin.Cell. 2014;158(4):929-944.
9. Ross et al., J Clin Oncol 32:5s, 2014 (suppl; abstr 11048)
10. Cohen, RL and Settleman J. From cancer genomics to precision oncology— tissue’s still an issue.Cell. 2014;157(7):1509-1514.
11. bioTheranostics. CancerTYPE ID. http://www.biotheranostics.com/ healthcare-professionals/hcp/ctid/. Accessed August 29, 2014.
12. Kerr SE, Schnabel C, Sullivan PS, et al. Multisite validation study to determine performance characteristics of a 92-gene molecular cancer classifier.Clin Cancer Res. 2012;18(14):3952-3960.
13. Hainsworth JD, Rubin MS, Spigel DR, et al. Molecular gene expression profiling to predict the tissue of origin and direct site-specific therapy in patients with carcinoma of unknown primary site: a prospective trial of the Sarah Cannon research institute.J Clin Oncol. 2013;31(2):217-223.
14. Thomas SP et al. Molecular profiling with the 92-gene assay and decision-impact on cancer treatment: Interim results from a prospective, multidisciplinary study.J Clin Oncol. 2015 (abstr 249).
15. Kim B, Schroeder B, Schnabel C, Erlander G, Malin JL. Physician-reported clinical utility of the 92-gene molecular classifier in tumors with uncertain diagnosis following standard clinicopathologic evaluation.Pers Med Oncol. 2013;2(2):68-76.
16. Life Technologies. Ion Torrent™. http://www.lifetechnologies.com/us/ en/home/brands/ion-torrent.html. Accessed August 29, 2014
17. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer.N Engl J Med. 2012;366(26):2443.
18. Brahmer JR, Horn L, Gandhi L, et al. Nivolumab (anti—PD-1, BMS-936558, ONO-4538) in patients (pts) with advanced non–small-cell lung cancer. Presented at the ASCO Meeting 2014. Chicago, IL. Abstract 8112.
19. Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer,N Engl J Med. 2013;368(25):2385.
20. Leighl NB, Rekhtman N, Biermann WA, et al. Molecular testing for selection of patients with lung cancer for epidermal growth factor receptor and anaplastic lymphoma kinase tyrosine kinase inhibitors: American society of clinical oncology endorsement of the college of american pathologists/ international society for the study of lung cancer/association of molecular pathologists guideline.J Clin Oncol. 2014;32(32):3673-3679.