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Pancreatic cancer is currently the fourth-leading cause of cancer death in the United States, with a 5-year survival rate of approximately 8%. Unfortunately, over the past decade, new cases have been increasing on average 0.5% a year, and pancreatic cancer is predicted to be the secondleading cause of cancer death by 2030.

In an effort to bend this mortality curve, the University of Texas Southwestern Medical Center and Harold C. Simmons Comprehensive Cancer Center in Dallas offer a far-reaching program aimed at detecting pancreatic malignancies early and/or preventing their development in high-risk patients. Currently, only 15% to 20% of patients present with an initially resectable tumor and more than half of pancreatic cancers are discovered after the cancer has widely metastasized.

In the UT Southwestern Pancreatic Cancer Prevention Program, radiologists, gastroenterologists, surgical oncologists, cancer genetic counselors, and other providers collaborate in a weekly clinic to evaluate patients with risk factors for pancreatic malignancies and to develop personalized treatment plans.

Patients in the program have an elevated risk for pancreatic cancer due to 1 or more of these risk factors:

A family history of pancreatic cancer or of other malignancies that can be linked to the disease

Genetic testing showing mutations associated with increased risk

Presence within the pancreas of 1 or more mucinous cysts

Malignant transformation of pancreatic cysts is relatively uncommon; 1 study estimates an annual US rate of just 0.033%, or about 1137 mucin-producing adenocarcinomas among some 3.4 million total pancreatic cysts.

 However, the current absence of sensitive diagnostic studies to detect progression to cancer limits the ability to truly assess risk for these patients. A core component of the Pancreatic Cancer Prevention Program is ongoing assessment of mucinous cysts for characteristics indicating that they have, or are likely to undergo, malignant transformation.

With a lifetime risk in the United States of 1.6%,

 pancreatic cancer is relatively rare, making universal screening impractical. However, patients with precursor mucinous cystic lesions and those with a hereditary risk represent enriched populations in which screening and surveillance could prove more impactful.

A pillar of the UT Southwestern/Simmons Cancer Center Prevention Program is the incidental discovery of pancreatic lesions on abdominal imaging and the use of electronic medical records to ensure that patients with these lesions are not lost to follow-up.

Radiologists at the medical center embed templated language into the patient’s radiology imaging report that flags the often-incidental finding of a pancreatic cyst or other abnormality. This automatically populates a registry within the electronic medical record for the prevention program’s nurse navigator to manage. The nurse navigator then initiates the process for further care, contacting the patient’s primary care and ordering physician for the study that identified the abnormality, providing referral and contact information for the prevention program, alerting program team members, and directing referring physicians to management guidelines for pancreatic abnormalities.

Patients referred from elsewhere access the prevention program through a patient intake specialist, who connects them with the nurse navigator. In collaboration with the program’s physician assistants, the navigator collects relevant internal and external medical records; reviews medical and family histories, plus any previous imaging and genetic tests; and gathers further details about cysts that have been detected and related symptoms, if present.

The program’s multidisciplinary team evaluates each case before a patient arrives for consultation. Any procedures needed to better visualize or sample a lesion, such as endoscopic ultrasound (EUS) or additional imaging, are scheduled in the interim, and appointments—all at 1 location&mdash;are set with the specific providers each patient needs to see.

Radiologists associated with the program are attuned to findings that may be indicative of cancer. These include whether a cyst has developed septations in its interior, whether the septations have changed since a prior examination, nodularity in the cyst’s walls, and whether the pancreatic duct is obstructed or dilated (Figure).

Figure. Pancreatic Cyst Surveillance Program

For patients who undergo EUS, cyst fluid can be sampled and assessed for molecular markers or other precancerous features, and solid masses can be examined for the presence of tumor cells or atypia. Patients with a malignancy are referred directly to UT Southwestern’s Multidisciplinary Pancreatic Cancer Program for treatment. With patient consent, cyst fluid and blood samples are banked and paired with clinical records to support future biomarker research.

Once testing is completed, cases are individually reviewed by a full range of specialists in the prevention program’s multidisciplinary conference. The conference includes the same group of experts reviewing each case over time, using imaging that is consistently acquired from visit to visit, allowing for optimal comparisons.

Because pancreatic cysts are clinically challenging, the multidisciplinary group utilizes an evidence-based approach to assess each patient’s personal risk and then recommends a consensus treatment plan. In a minority of cases, the team will recommend removal of a portion or all of the pancreas to prevent the development of pancreatic cancer, or to treat lesions within or throughout the pancreas that are suspicious. More often, customized, long-term surveillance is recommended, and the patients are followed within the program at 6-month to 1-year intervals, depending on the level of concern.

The prevalence of pancreatic cysts noted on imaging typically performed for unrelated reasons is quite high. One study from a major center4 suggests that the rate of incidental detection of pancreatic cysts with magnetic resonance imaging (MRI) is 13.5%, and in patients age 70 and older the cumulative prevalence was 40%.

Although most cysts are benign, 2 types of mucinous cysts are considered potentially premalignant: intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs). IPMNs can affect the entire pancreas, sometimes necessitating complete removal of the organ to excise all at-risk tissue. More frequently, only portions of the pancreas are involved, although ongoing surveillance is required because cystic lesions or pancreatic cancer can develop in the remnant gland post operatively. MCNs are less-common and are unifocal; following their surgical resection, ongoing surveillance of the remaining pancreas is not required if margins were not involved and there was no evidence of cancer.

Along with the structural features of a cyst, decisions to operate hinge on the presence of symptoms such as pancreatitis, involvement of the main pancreatic duct, and rapid growth of a cyst. Cysts larger than 3 cm also warrant closer attention, but size alone is not an indication for resection.

Several hereditary cancer syndromes involve increased pancreatic cancer risk. These include mutations in the BRCA1 or BRCA2, P16/CDKN2A, or STK11 genes, Lynch syndrome, familial pancreatic cancer, and mutations associated with hereditary pancreatitis.

In appropriate patients, genetic testing is recommended to look for mutations in more than a dozen genes linked to pancreatic cancer, plus several associated with hereditary pancreatitis. Patients with a hereditary risk are counseled on lifestyle changes, such as quitting smoking and ceasing alcohol consumption. Such patients might also undergo annual MRI surveillance of the pancreas to identify any subtle changes that suggest the development of a potential cancer.

Prevention and surveillance measures can also be implemented for the other cancers linked to a hereditary syndrome, such as mammography or breast MRI in people with BRCA mutations, colonoscopy in Lynch syndrome, and skin cancer screenings and sun protection in familial atypical multiple mole melanoma syndrome. The prevention program’s genetic counselors also guide patients on how to talk with family members regarding the potential indications for and benefits of genetic testing.

Since the launch of UT Southwestern’s Pancreatic Cancer Prevention Program in January 2016, more than 350 patients with increased risk for pancreatic cancer have been evaluated. Two-thirds of these patients were referred for cystic neoplasms of the pancreas and approximately one-third for high-risk hereditary conditions.

Through this program, patients have been found to have previously unknown germline mutations predisposing them to pancreatic cancer, as well as high-risk lesions that were successfully resected prior to development of pancreatic cancer. The next step in preventing this disease is the identification of biomarkers that can predict which patients are at highest risk; programs such as this one will provide a platform for that critically important work.

SEER cancer stat facts: pancreas cancer. National Cancer Institute website. seer.cancer.gov/statfacts/html/pancreas.html. Published April 2017. Accessed July 6, 2017.

Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM. Projecting cancer incidence and deaths to 2030: The unexpected burden of thyroid, liver, and pancreas cancers in the United States [erratum in Cancer Res. 2014;74(14):4006]. Cancer Res. 2014;74(11):2913-1921. doi: 10.1158/0008-5472. CAN-14-0155.

Gardner TB, Glass LM, Smith KD, et al. Pancreatic cyst prevalence and the risk of mucin-producing adenocarcinoma in US adults. Am J Gastroenterol. 2013;108(10):1546-1550. doi: 10.1038/ ajg.2013.103.

Lee KS, Sekhar A, Rofsky NM, Pedrosa I. Prevalence of incidental pancreatic cysts in the adult population on MR imaging. Am J Gastroenterol. 2010;105(9):2079-2084. doi: 10.1038/ajg.2010.122.

Articles

Pancreatic cancer is currently the fourth-leading cause of cancer death in the United States, with a 5-year survival rate of approximately 8%.

Prevention Program Targets Pancreatic Cancer Before It Gains a Foothold

A novel combination therapy aimed at 2 processes implicated in 

mutant melanoma has displayed promising activity in preclinical investigations, signaling an avenue of exploration for a new therapeutic approach for patients who currently have few options.

Researchers at the Wistar Institute in Philadelphia have paired BET and MEK inhibitors for testing in biopsy samples from patients treated for metastatic melanoma and in several types of mouse models. The responses to the combination in 

-mutant disease have been “striking,” according to Jessie Villanueva, PhD. The combination inhibited the growth of tumors and prolonged the survival of the mice without adverse effects such as weight loss and lethargy and without negative histopathological impact on the lung, liver, spleen, or kidney.

Villanueva presented an overview of the novel strategy during the Noreen O’Neill Melanoma Research Symposium held June 20 at the Wistar Institute. “We’re very excited about this combination,” said Villanueva, who is an assistant professor in the Molecular and Cellular Oncogenesis Program and a member of the Wistar Institute Melanoma Research Center. “We think it’s a promising strategy and we hope that it can be translated, perhaps as a salvage strategy for those patients who have failed both immunotherapy and targeted therapy.”

Dual targeted therapy approaches for the treatment of patients with melanoma have proliferated in recent years, starting in 2014 with the FDA’s approval of the combination of trametinib (Mekinist) and dabrafenib (Tafinlar) for patients with unresectable or advanced melanoma with a 

 V600E or V600K mutation. Next, in November 2015, the FDA approved cobimetinib (Cotellic) in combination with vemurafenib (Zelboraf) for a similar patient population. Recent phase III findings support the efficacy of a third combination, encorafenib and binimetinib, which is now undergoing an FDA review for a similar patient population.

These pairings combine BRAF inhibitors (dabrafenib, vemurafenib, encorafenib) with MEK inhibitors (trametinib, cobimetinib, binimetinib) and are aimed at patients with BRAF mutations, which have been found in 37% to 50% of melanoma samples.

Although these combinations attack 2 targets, both BRAF and MEK are components of the mitogen-activated protein kinase (MAPK) signaling pathway that is central to driving the proliferation of cancer cells (Figure A).

 These kinases are often driven by RAS oncogenes, which have been implicated in more than 30% of all human cancers. Mutations in NRAS, a member of the RAS family, have been identified in 13% to 25% of melanomas.

Figure A. RAS Signaling and Downstream Targets

There are no therapies targeting NRAS mutations, and this constitutes an urgent, unmet need for patients with melanoma, said Villanueva. “

-mutant tumors are extremely aggressive,” she said. “They rapidly metastasize to the lymph nodes, glands, and other organs.”

Villanueva and colleagues, including Ileabett Echevarria-Vargas, PhD, analyzed data from The Cancer Genome Atlas and learned that BRD4, a member of the bromodomain and extra-terminal domain (BET) family of proteins, was expressed at relatively high levels in 

-mutant tumors. BRD4 expression correlated with patient outcomes, as lower levels were associated with higher survival rates. “BRD4 plays a major role in regulating proliferation in these cells,” said Villanueva.

To test their hypothesis, researchers used 2 investigational BET inhibitors: JQ1 and OTX015. JQ1 was discovered at the Dana-Farber Cancer Institute; the Roche Group is developing a chemically similar compound, TEN-010.

 Meanwhile, Merck is developing OTX015 under the name MK-8628. For the MEK inhibitor, investigators used PD0325901.

Villanueva said the BET inhibitors have been well characterized in prior research (Figure B

) and that the MEK-targeting agent is an older drug that was commercially available.

As with other anticancer strategies, researchers found that the inhibitors were not effective as monotherapy but showed impressive preclinical activity when paired and used against 

-mutant melanoma with high BRD4 expression. “Targeting a single pathway or a single oncogene doesn’t really lead us to effective responses,” noted Villanueva.

BET proteins are epigenetic regulators of genetic material packaged in the form of chromatin, which is composed of negatively charged DNA wound tightly around positively charged histone proteins like thread on a spool. BRD4 is an epigenetic “reader” that binds to marks in the chromatin that signal the transcription complex, Villanueva explained in an interview with 

As a result, pairing BET and MEK represents dual targeted therapy aimed at 2 types of signaling, as opposed to 2 junctures in the same pathway offered by current combinations.

“The approach that we’re taking is slightly different in the sense that we’re hitting 2 different pathways that are somewhat interrelated,” said Villanueva. “One of them is the MAPK pathway, which is critical for melanoma. Basically, all types of melanomas depend on this pathway. We need to target that.

“On top of that, we’re targeting the BET protein, which regulates multiple transcriptional effects,” she added. “By doing that, we think we are perturbing the transcriptional profile of the cells so that the cells are not robust. They can now accept a second hit and be much more sensitive to [that] hit.”

The experiments at Wistar come at a time when epigenetic processes are attracting increasing interest in the development of anticancer therapy. At least 10 BET inhibitors are being evaluated in phase I and II trials in a range of hematologic and solid malignancies, including acute myeloid leukemia, myelodysplastic syndrome, and glioblastoma.

Additionally, histone deacetylases, enzymes that function in the epigenetic process by repressing gene transcription, are being explored. One novel combination under study involves pairing of pembrolizumab (Keytruda), a PD-1 inhibitor, with entinostat, an HDAC inhibitor.

Today, the research conducted on the BET/MEK inhibitor combination is not directly paired with a particular drug or clinical development program, but Wistar is exploring collaboration opportunities to see these findings translated into the clinic in the future.

Wistar is a National Cancer Institute—designated Cancer Center. The symposium where Villanueva presented her findings was sponsored by the Noreen O’Neill Melanoma Foundation for Melanoma Research, which was founded by a Philadelphia executive who was diagnosed and later succumbed to malignant melanoma.

Lovly C, Pao W, Sosman J. Molecular profiling of melanoma. My Cancer Genome website. http://goo.gl/YrX6v4. Updated January 26, 2016. Accessed July 9, 2017.

Nussinov R, Jang H, Tsai CJ. The structural basis for cancer treatment. 

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Von Schaper E. Roche bets on bromodomains. 

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Fu L, Tian M, Li X, et al. Inhibition of BET bromodomains as a therapeutic strategy for cancer drug discovery. 

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A novel combination therapy aimed at 2 processes implicated in NRAS-mutant melanoma has displayed promising activity in preclinical investigations, signaling an avenue of exploration for a new therapeutic approach for patients who currently have few options.

Novel Therapy Partners Emerge in Melanoma Research

A new test that can detect the existence of tumor activity is gaining credibility as a means of confirming the results of prostate biopsies, which have the potential to miss tumor cells. The ConfirmMDx epigenetic assay from MDxHealth, of Belgium, hunts for signs of DNA methylation, and recent study results have confirmed its value. One study in particular, involving African American men, was presented in May at the American Urological Association (AUA) annual meeting and demonstrated strong negative predictive value.

Prostate biopsies not only are invasive and uncomfortable for patients, but also carry significant risk for patients, who may suffer bleeding, pain, difficult or painful urination, and infection and may have blood in the urine or semen.

 These factors can make it challenging for urologists and patients to decide whether a second prostate biopsy is necessary if the initial test is inconclusive.

Further, prostate biopsies sometimes produce false-negative results due to the limitations of the current standard of care—a 12-core needle transrectal ultrasound-guided biopsy. “The challenge is that it is a relatively random sampling because although they’re trying to sample 12 definitive areas of the prostate, the needle may not always end up where it’s supposed to be,” explained Christopher Thibodeau, chief operating officer and EVP of MDxHealth, in an interview with 

Although the biopsy is targeted for areas of most probable activity, it can still amount to a proverbial shot in the dark. “We’re sampling less than 1% of the prostate, so when we look at the men who are undergoing biopsies, most urologists would argue that there is a chance the biopsy might have missed something,” Thibodeau said.

The ConfirmMDx assay is efficient in that it can analyze the same tissue removed during a biopsy and potentially detect cancer even if tumor cells are not present in the sample. Typically, if after a prostate biopsy, a urologist still feels that the patient may be at risk for cancer—for example, based on results of a digital rectal exam or prostate-specific antigen (PSA) test&mdash;a second biopsy and perhaps even more could be performed. However, additional biopsies could compound the risk of bleeding and infection, lengthen recovery time for the patient, and cause patients to become frustrated with the process.

ConfirmMDx is an alternative to a string of repeat biopsies and their associated risks. “Around the area where the cancer cells are, there are changes happening,” said Wim Van Criekinge, PhD, chief scientific officer of MDxHealth and a professor at the University at Ghent in Belgium. “One of these changes is the DNA gets modified by being near the cancer cells. The cells containing that modified DNA have not [yet] become cancer cells themselves—that’s why the biopsy doesn’t recognize them as being abnormal. The molecular test can see the changes before they progress to a morphological level.”

Specifically, ConfirmMDx tests for methylation of the 

 genes, which are widely studied prostate cancer biomarkers that give an indication not only of the presence of cancer, but the aggressiveness of that cancer as well. Demonstrating confidence in the assay, the National Comprehensive Cancer Network (NCCN) this year recommended ConfirmMDx as a tool for early detection of prostate cancer. An NCCN panel stated that the assay “can be considered an option for men contemplating repeat biopsy because the assay may identify individuals at higher risk of prostate cancer diagnosis on repeat biopsy.”

Improving Diagnosis in African American Men

Specifically, the NCCN guidelines recommend the test for patients who have had at least 1 prior negative biopsy and are thought to be at higher risk, particularly when assessing their PSA levels. Other options listed for patients with a prior negative biopsy are percent- free PSA, the Prostate Health Index, the 4Kscore test, and a prostate cancer antigen 3 (PCA3) test.

The recent trial results showing that ConfirmMDx has predictive value among African American men suggest the potential for improved treatment in this population, which is underserved when it comes to prostate cancer diagnosis and therapy. African American males have a greater risk of clinically significant prostate cancer than the general population, and prostate cancer in this racial grouping tends to have a different molecular structure. They are approximately 1.6 times more likely than Caucasians and 2.7 times more likely than Asian Americans to develop the disease.

Prior study results have shown the clinical utility of ConfirmMDx among other populations, too, but until the study presented at the AUA meeting this year, data were lacking on how the assay would perform specifically in the African American population. Principal investigator Robert L. Waterhouse Jr, MD, MBA, and his colleagues wanted to make sure that the test would help African American patients avoid unnecessary repeat biopsies.

Eligible patients were African Americans who had an initial negative prostate biopsy, without any atypical glands or other findings that would increase the risk of having prostate cancer, and a second prostate biopsy within 30 months of the initial biopsy. The ConfirmMDx test was then performed on the tissue from the first biopsy, and investigators checked the results against the findings from the second biopsy.

For each patient included in the study (n = 211), a median of 12 cancer-negative biopsy cores were analyzed. Upon repeat biopsy, 55% of patients had no prostate cancer detected, while 45% received the diagnosis.1 ConfirmMDx improved the identification of African American men at risk for aggressive cancer missed by the initial prostate biopsy. The assay achieved a negative predictive value of 91.2% for any prostate cancer found on rebiopsy. The negative predictive value for high-grade cancer, defined as Gleason 7 or higher, was 96%. Higher intensities were also observed for men diagnosed with highgrade prostate cancer relative to those men with no prostate cancer detected upon biopsy (

Essentially, Waterhouse said, the results showed that a negative result on the ConfirmMDx test means there is a low likelihood that disease will be found in a second biopsy. “If someone has the test performed to look at methylation of all 3 genes on the initial prostate biopsy tissue, and no methylation is found in any of the 3 genes, in any of the 12-core biopsy specimens, then if they were to undergo a repeat prostate biopsy, they have a less than 9% likelihood that prostate cancer will be found at all and a less than 4% likelihood that high-grade cancer would be found,” Waterhouse, a practicing urologist at Carolina Urology Partners in North Carolina, explained.

There may be highly valid reasons for going forward with repeat biopsies, but the results of the trial indicate the strong clinical value of ConfirmMDx. “If the initial prostate biopsy is negative, and we perform this test and it’s negative, then we have a greater degree of comfort that a repeat biopsy does not have to be performed,” said Waterhouse.

Researchers have also sought to determine the clinical utility of the ConfirmMDx assay to detect occult prostate cancer in negative biopsies. In the MATLOC study, investigators blindly tested archived prostate biopsy needle core tissue samples from 498 subjects in the United Kingdom and Belgium with histopathologically negative prostate biopsies. Initial biopsies were tested with the assay and the second biopsies were used for confirmation of the assay’s efficacy.

The epigenetic assay tested on negative biopsies resulted in a negative predictive value of 90% (95% CI, 87%-93%). In a multivariate model factoring for patient age, PSA level, digital rectal examination results, and histopathological characteristics of the initial biopsies, ConfirmMDx was found to be a statistically significant independent predictor of patient outcome, with an odds ratio of 3.17 (95% CI, 1.81-5.53).

The investigators also found that ConfirmMDx accurately identified 64% of patients without prostate cancer who could safely avoid a repeat biopsy. Notably, the test correctly identified 68% of men who were harboring undetected prostate cancer at the time of their previous histopathologically negative biopsy. Many of those patients presented with clinically significant cancer upon repeat biopsy that would qualify for aggressive treatment.

The DOCUMENT study, a multicenter trial in the United States, also validated ConfirmMDx as an independent predictor of prostate cancer risk to guide decision making for repeat biopsy. As they did for the MATLOC study, investigators evaluated archived negative prostate biopsy core tissue samples from 350 patients, all of whom underwent a repeat biopsy within 24 months and were found to be positive or negative for cancer.

 The samples from the first biopsies were tested for the 

genes. According to Thibodeau, 13% of the participants included in the DOCUMENT study were African American, so this was an early indication that the assay would perform well in this population.

In this trial, the assay demonstrated a negative predictive value of 88% (95% CI, 85%-91%). In multivariate models factoring for age, race, PSA, digital rectal examination results, and histopathological characteristics of the first biopsy, the test proved to be the most significant independent predictor of patient outcome, with an odds ratio of 2.69 (95% CI, 1.60-4.51). These results validated that the assay was a significant independent predictor of prostate cancer detection in a repeat biopsy collected an average of 13 months after an initial negative result.6

Waterhouse RL Jr, Van Neste L, Barnswell C, et al. Clinical performance of an epigenetic assay to identify occult high-grade prostate cancer in African American men [AUA abstract PD07-04]. jurology. com/article/S0022-5347(17)30603-1/abstract.

Mayo Clinic Staff. Prostate biopsy: risks. Mayo Foundation for Medical Education and Research website. mayoclinic.org/tests-procedures/ prostate-biopsy/details/risks/cmc-20200186. Accessed June 14, 2017.

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) Prostate Cancer Early Detection Version 1.2017. nccn.org/professionals/physician_gls/pdf/prostate_detection.pdf. Published June 5, 2017. Accessed June 14, 2017.

Age-Adjusted SEER Incidence Rates by Race and Sex, Prostate, All Ages. Surveillance, Epidemiology, and End Results (SEER) database, 2000-2014. National Cancer Institute. seer.cancer.gov/faststats/ selections.php?#Output. Accessed June 14, 2017.

Stewart GD, Van Neste L, Delvenne P, et al. Clinical utility of an epigenetic assay to detect occult prostate cancer in histopathologically negative biopsies: results of the MATLOC study. 

 2013;189(3):1110-1116. doi: 10.1016/j.juro.2012.08.219.

Partin AW, Van Neste L, Klein EA, et al. Clinical validation of an epigenetic assay to predict negative histopathological results in repeat prostate biopsies. 

 2014;192(4):1081-1087. doi: 10.1016/j.juro.2014.04.013.

A new test that can detect the existence of tumor activity is gaining credibility as a means of confirming the results of prostate biopsies, which have the potential to miss tumor cells.

Epigenetic Assay Could Spare Patients From Additional Biopsies for Prostate Cancer

Two combination regimens anchored by different proteasome inhibitors are being compared in a national clinical trial for patients with newly diagnosed symptomatic multiple myeloma (MM) that also seeks to evaluate the ideal duration of lenalidomide (Revlimid) maintenance therapy.

The phase III ENDURANCE trial (NCT01863550), which is currently enrolling and has accrued nearly 600 patients, will randomize participants to receive lenalidomide and dexamethasone with either bortezomib (Velcade) or carfilzomib (Kyprolis) for 9 months, followed by lenalidomide maintenance therapy administered either indefinitely or for 2 years (

The primary endpoint of the trial is overall survival (OS) for the maintenance analysis. Secondary endpoints include progression-free survival (PFS) for the maintenance phase and PFS for the induction stage.

“At this point, we don’t know how long [lenalidomide maintenance] needs to be given, so this time we’re going to look at whether 2 years is sufficient or if we need to give it longer. This will definitely have clinical value because if we can get away with limited duration of treatment, it helps reduce costs and also helps reduce toxicity,” said Shaji Kumar, MD, a professor of medicine at Mayo Clinic in Rochester, Minnesota, who is the national principal investigator for the trial.

  The study is open to patients with newly diagnosed, stage I-III MM who have not received prior treatment for their disease. The trial will enroll patients categorized as standard risk, with no evidence of high-risk chromosomal abnormalities, which are defined as the translocations t(4;14), t(14;16) and t(14;20) or deletion 17p. Patients cannot have received more than 1 cycle of prior chemotherapy and no more than 160 mg of prior dexamethasone for treatment of symptomatic myeloma. They also should not have been treated with lenalidomide, bortezomib, or carfilzomib.

“Patients who are eligible can undergo a stem cell collecton for transplantation at the time of disease relapse, and then can continue on the trial as planned,” explained Kumar. Only patients who are at standard-risk are eligible for this study because there is a parallel trial investigating high-risk patients.

In comparing induction strategies, the study is evaluating triplet regiments containing bortezomib and carfilzomib, the competing proteasome inhibitors. Although both agents affect the same 26S proteasome target, bortezomib is a reversible inhibitor, whereas carfilzomib is not. Due to this difference, investigators are interested in seeing whether carfilzomib can more effectively kill tumor cells or block them from dividing, making it a potentially better treatment for patients with MM.

The combination of bortezomib with lenalidomide and dexamethasone has become a standard regimen as primary therapy for transplant and nontransplant candidates, and carries a category 1 recommendation in the National Comprehensive Cancer Network guidelines.

 Carfilzomib, a second-generation proteasome inhibitor that the FDA has approved in the relapsed and refractory settings, has demonstrated high PFS rates in newly diagnosed patients in phase I-II clinical trials, resulting in a category 2A option as a primary treatment for transplant-eligible patients.

 The most common adverse events (AEs) associated with bortezomib have been decreases in blood counts, particularly platelet counts; peripheral neuropathy; and increased risk of infections. For carfilzomib, common AEs include drops in blood counts, increased risk of infections, and fatigue. There also was a higher incidence of cardiac failure with the combination of carfilzomib and dexamethasone versus bortezomib and dexamethasone in a previous clinical trial.

 In the head-to-head portion of the ENDURANCE trial, investigators will be closely monitoring patients for these AEs, Kumar said.

The ENDURANCE trial is being sponsored by the ECOG-ACRIN Cancer Research Group, with collaboration from the National Cancer Institute. Bortezomib is developed by Takeda Oncology, and carfilzomib is developed by Amgen Inc.

NCCN clinical practice guidelines in oncology: multiple myeloma version 3.2017. National Comprehensive Cancer network website. nccn.org/professionals/physician_gls/pdf/myeloma.pdf. Updated November 28, 2016. Accessed July 10, 2017.

Kyprolis [prescribing information]. Thousand Oaks, CA: Onyx Pharmaceuticals, Inc; 2017.

Two combination regimens anchored by different proteasome inhibitors are being compared in a national clinical trial for patients with newly diagnosed symptomatic multiple myeloma that also seeks to evaluate the ideal duration of lenalidomide (Revlimid) maintenance therapy.

Myeloma Trial Explores Optimal Induction, Maintenance Regimens

After years of efforts to steer clinical trials toward molecularly defined therapeutic targets, oncology researchers recently notched 2 key successes in changing the paradigm of how patients with advanced cancers are diagnosed and treated:

On May 23, the FDA approved pembrolizumab (Keytruda) for the treatment of patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors, marking the first time a drug gained an indication based on its efficacy against a molecular target rather than on the primary tumor site.

On June 3, investigators reported that 78% of patients with 

 fusion—positive cancers responded to treatment with larotrectinib (LOXO-101), potentially making the drug the first targeted therapy developed in a “tumor agnostic” manner.

Oncology experts have described these developments as important milestones on the road to personalized medicine. At the same time, the complexities involved with translating such molecular breakthroughs into broader research protocols and clinical practice have quickly become a matter of discussion.

Although most somatic genetic aberrations can be found in multiple tumor types, preclinical models are not adequately constructed to reflect sensitivity to potential new agents in tumor microenvironments across histologies, Flaherty and colleagues cautioned in an article in the 

Moreover, laboratory experience has shown that primary tumors may respond differently to a targeted therapy even if they share a molecular defect, the researchers noted. “Every drug presents unique circumstances in regard to the population of patients who might benefit from it,” they wrote. “Furthermore, development agnostic of tumor type could actually slow drug development if there are differential effects across tumor types by diverting resources from enrolling patients in a predominant population or in the tumor type most like to respond.”

A notable example of disparate results from targeting the same mutation in multiple tumor types is the 

 mutation. “The BRAF inhibitor works in 100% of the histiocytosis patients who have 

mutations, but it only works in about 60% of the melanoma patients, and about 40% of lung cancer patients, and it never works alone in colorectal cancers,” said David B. Solit, MD, in an in interview with

“So it’s the same drug and the same exact 

 V600E mutation, but that drug works differentially depending upon what cancer type you have because each of those cancers has co-mutation patterns and other lineage-specific factors that are true because of the development of those cell contexts,” said Solit, who is the Geoffrey Beene Chair and director of the Marie-Josée and Henry R. Kravis Center for Molecular Oncology at Memorial Sloan Kettering (MSK) Cancer Center in New York City.

Nevertheless, Solit said he believes the evidence for the utility of targeted therapies across tumor types has made broad genomic sequencing of patients’ tumors a necessity. “The pembrolizumab data in particular with the MSI status makes genomic analysis of every patient’s tumor now important to do just from a standard-of-care perspective,” he said. “If you don’t do it, you’re going to miss something that that patient could have responded to.”

The major barrier to conducting such testing for every patient is that payers are balking at covering the cost of next-generation sequencing (NGS), as opposed to single-gene testing, without an approved targeted agent linked to the assays, according to Solit and other experts.

Gordon B. Mills, MD, PhD, a pioneer in the field of molecularly targeted anticancer therapies, said a “culture shift” is necessary to build support for covering such testing.

“I think we’ve known for quite a while that many drugs work beyond the original tumor that they were identified in,” said Mills, who is chair of the Department of Systems Biology and head of the Kleberg Center for Molecular Markers at The University of Texas MD Anderson Cancer Center in Houston, in an interview. “The question is whether we’re going to able to leverage the MSI approval and the [larotrectinib data], and some of the other ones that will come down the pipeline soon across diseases, to justify broad testing of all patients, or at least all patients likely to benefit.”

Mills said sequencing can cost $2000 to $3000 per patient at MD Anderson, but the reimbursement from CMS can be as low as $50. “How does one balance the need to do the testing to acquire the information to say that this really does benefit patients and should be paid for versus the pushback from industry and CMS saying until you know exactly how to use it we find it is far too expensive and not sustainable?”

From a research standpoint, Mills sees the MSI approval of pembrolizumab and the molecularly focused development of larotrectinib as © ©ktsdesign/fotolia.com “incredibly exciting.”

“The key question over the next 6 months to a year is, are we going to be able to leverage them to help the breadth of patients that we should be able to help with these technologies?” Mills said.

The FDA’s recognition of dMMR as the first predictive biomarker for a targeted therapy across tumor types is built upon a “strong biologic rationale, availability of commercially used diagnostics for patient identification, and the urgent, unmet medical needs of patients with refractory cancers,” Flaherty et al contended.

Specifically, the FDA has granted an accelerated approval to pembrolizumab for the treatment of adult and pediatric patients with unresectable or metastatic MSI-H or dMMR solid tumors that have progressed after prior treatment and who have no satisfactory alternative treatment options, as well as for patients with MSI-H or dMMR colorectal cancer (CRC) following progression on a fluoropyrimidine, oxaliplatin, and irinotecan.

The approval for the PD-1—targeting immunotherapy agent was based on data from 149 patients with MSI-H or dMMR cancers enrolled across 5 single-arm clinical trials. Ninety patients had CRC and the remaining 59 had 1 of 14 other tumor types (Figure).

Overall, the objective response rate (ORR) with pembrolizumab was 39.6% (95% CI, 31.7%-47.9%), including 11 (7.4%) complete responses (CRs) and 48 (32.2%) partial responses (PRs). The ORR was 36% in patients with CRC; it ranged from 27% to 83% in patients with other tumor types (Table, page 19; Figure). The median duration of response for the entire population was not yet reached (range, 1.6 -22.7 months). Among patients who responded to pembrolizumab, 78% had responses that lasted for at least 6 months.

“This is an important first for the cancer community,” said Richard Pazdur, MD, acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research and director of the FDA’s Oncology Center of Excellence, in a statement announcing the approval. “Until now, the FDA has approved cancer treatments based on where in the body the cancer started—for example, lung or breast cancers. We have now approved a drug based on a tumor’s biomarker without regard to the tumor’s original location.”

The pivotal data for the approval included patients from the KEYNOTE-016 (n = 58), KEYNOTE-164 (n = 61), KEYNOTE-012 (n = 6), KEYNOTE-028 (n = 5), and KEYNOTE-158 (n = 19) trials. Pembrolizumab was administered at 200 mg every 3 weeks or 10 mg/kg every 2 weeks until disease progression, unacceptable toxicity, or a maximum of 24 months.

The median age among the 149 patients was 55 years, with 36% aged 65 or older. Across the population, 77% of patients were white, 56% were male, 36% had an ECOG performance status (PS) of 0, and 64% had an ECOG PS of 1.

Two percent of patients had locally advanced, unresectable disease, and 98% of patients had metastatic disease. Among patients with metastatic or unresectable disease, the median number of prior therapies was 2. In patients with metastatic CRC, 84% had received at least 2 prior lines of therapy compared with 53% in patients with other solid tumors.

Among the majority (n = 135) of the 149 patients, MSI-H or dMMR tumor status was determined prospectively with immunohistochemistry tests for dMMR or laboratory-developed, investigational polymerase chain reaction (PCR) tests for MSI-H status. For the remaining 14 patients, MSI-H status was determined through a retrospective evaluation of 415 tumor samples using a central laboratory-developed PCR test.

In its statement on the approval, the FDA listed common adverse events (AEs) of pembrolizumab, including fatigue, pruritus, diarrhea, decreased appetite, rash, pyrexia, cough, dyspnea, musculoskeletal pain, constipation, and nausea. Immune-mediated AEs associated with pembrolizumab include pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis.

The FDA also noted that the label for pembrolizumab includes a “Limitation of Use” indicating that the efficacy and safety of pembrolizumab have not been established in pediatric patients with MSI-H central nervous system cancers. The accelerated approval for pembrolizumab in this setting is contingent on the results of a confirmatory trial. The approval was preceded by a breakthrough therapy designation the FDA granted to pembrolizumab in November 2015 as a treatment for patients with MSI-H metastatic CRC.

“The main data here are showing that in CRC and non-CRC, we’re seeing response rates with pembrolizumab that are quite impressive,” Luis A. Diaz Jr, MD, whose research helped paved the way for the pembrolizumab approval, said in an interview. “The progression-free survival and overall survival are quite durable, and it’s recapitulated in entirely different studies. I believe that is what led to the FDA approval.

“What’s impressive about the FDA approval is that it is not only across all tumor types, but it is in adults and children,” added Diaz, head of the Division of Solid Tumor Oncology at MSK. “It’s the first time that we’re no longer looking at tumors by the site of origin, but rather by the genetic lesion. This is incredibly exciting and is a historic approval by the FDA. In my opinion, it will knock down the walls of how we think about cancer in the future.”

Now, he added, “the challenge is to get everyone tested. I think that is the first step.”

Findings for larotrectinib were among the clinical trial results that generated the most excitement at the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting in June. Three of 4 patients representing a range of TRK fusion—positive solid tumors responded to the novel pan-TRK inhibitor larotrectinib and remain on treatment, setting the stage for the well-tolerated oral agent to become a standard of care for adults and children with any advanced tumor harboring this mutation.

“You would be hard-pressed to find a targeted therapy, even within a single disease context, that has results like this,” said David Hyman, MD, chief of early drug development at MSK, who reported the findings during a press conference.

Larotrectinib is currently the only selective pan-TRK inhibitor in clinical trials, he pointed out. The oral small molecule is being developed by Loxo Oncology Inc under a breakthrough therapy designation that the FDA granted in July 2016.

Hyman said that larotrectinib also may be “the first cancer therapy ever developed simultaneously in both adults and children.” The trial data presented at ASCO involved 12 pediatric and 43 adult patients ranging in age from 4 months to 76 years.

TRK fusions occur when 1 of the TRK genes becomes abnormally connected to another gene. This fusion event causes the TRK gene to be turned on and the cancer to grow. Although it is estimated that TRK fusion mutations could be found in up to 5000 patients each year, Hyman stressed that “this number may significantly underestimate its prevalence due to inadequate ascertainment by many of the existing profiling technologies.”

ASCO reported that TRK fusions were first discovered in colon cancer in 1982, but only recently has NGS enabled them to be systematically detected. To date, more than 50 different partner genes that fuse with 1 of 3 TRK genes (NTRK 1, 2, and 3) have been identified.

Hyman explained that TRK fusions typically follow 2 patterns: in adults, they occur rarely in more common cancers, such as brain, lung, colon, pancreatic, sarcoma, and melanoma; or, they occur more frequently in rare cancers, such as salivary and secretory breast cancer. This pattern also prevails in the pediatric setting, where the mutation is rarely seen in glioma and sarcoma, but more frequently in infantile fibrosarcoma and congenital nephroma.

Although relatively rare, Hyman said that it is hard to find a tumor type where TRK fusions have not been reported. “One of the defining features of TRK fusions is that they are not just found in one cancer type, but can be found in dozens of different cancer types—and in both children and adults.”

The study Hyman reported on at ASCO involved 55 TRK fusion—positive adult and pediatric patients with advanced solid tumors representing 17 unique cancer types who were enrolled in 1 of 3 clinical phase I/II clinical trials. Hyman emphasized that the patients were identified on the basis of local testing, and thus provide an example of “real world” experience: “We did not perform central screening to find the TRK fusions; in fact, 15 different laboratories identified the 55 patients who are described in this study.”

Hyman reported the ORR based on investigator assessment for 50 patients for whom confirmatory response data were available; larotrectinib (100 mg) was taken twice daily. The ORR was 76% (95% CI, 62%-87%), and this includes a PR in 64% of patients and a CR in 12%. Five additional patients, who joined the study too early to have had their confirmatory scans, all had at least a PR to larotrectinib, Hyman noted. He said most of the patients classified as having a PR “were not just meeting criteria for partial response, but had very deep tumor regressions.”

Echoing other oncology experts, Hyman said the larotrectinib data illustrate the benefits of broad mutation testing. “These findings embody the original promise of precision oncology: treating a patient based on the type of mutation, regardless of where the cancer originated,” Hyman said.

“We believe that the dramatic response of tumors with TRK fusions to larotrectinib supports widespread genetic testing in patients with advanced cancer to see if they have this abnormality.”

Keytruda [prescribing information]. Whitehouse Station, NJ: Merck & Co, Inc; 2017

Hyman DM, Laetsch TW, Kummar S, et al. The efficacy of larotrectinib (LOXO-101), a selective tropomyosin receptor kinase (TRK) inhibitor, in adult and pediatric TRK fusion cancers [ASCO abstract LBA2501]. J Clin Oncol. 2017;35(suppl). abstracts.asco. org/199/AbstView_199_195112.html.

Flaherty KT, Le DT, Lemery S. Tumor-agnostic drug development. Am Soc Clin Oncol Educ Book. 2017;37:222-230. doi: 10.14694/ EDBK_173855.

FDA approves first cancer treatment for any solid tumor with a specific genetic feature [news release]. Silver Spring, MD: US Food and Drug Administration; May 23, 2017. www.fda.gov/ NewsEvents/Newsroom/PressAnnouncements/ucm560167.htm. Updated May 24, 2017. Accessed July 10, 2017.

After years of efforts to steer clinical trials toward molecularly defined therapeutic targets, oncology researchers recently notched 2 key successes in changing the paradigm of how patients with advanced cancers are diagnosed and treated.

Beyond Tumor Type: New Milestones on a Long Road

The explosion of new checkpoint immunotherapy drugs has changed the paradigm of care for patients with urothelial carcinoma, the most common form of bladder cancer, according to experts who participated in a recent OncLive

 panel. Although chemotherapy regimens may still be the best first-line approach for some patients, other patients may benefit more from a checkpoint inhibitor.

Since May 2016, the FDA has approved 5 immunotherapy agents for patients with urothelial carcinoma: avelumab (Bavencio), atezolizumab (Tecentriq), durvalumab (Imfinzi), nivolumab (Opdivo), and pembrolizumab (Keytruda). The drugs, which are all PD-1 or PD-L1 inhibitors, have all been approved for patients with locally advanced or metastatic urothelial carcinoma that has progressed during or after platinum-containing chemotherapy, including within 12 months of neoadjuvant or adjuvant treatment. Atezolizumab and pembrolizumab also are indicated for patients who are not eligible for cisplatin-containing chemotherapy. Other checkpoint inhibitors that inhibit PD-1/PDL-1 or cytotoxic T-lymphocyte—associated antigen-4 (CTLA-4) have also shown activity in urothelial carcinoma.

 moderator Daniel P. Petrylak, MD, and other experts in the field of genitourinary oncology discussed how immunotherapy is changing outcomes for patients with advanced bladder cancer.

“Bladder cancer is a very heterogeneous disease, even within the metastatic state,” Petrylak said. Bladder cancers are broadly described as papillary or nonpapillary.

 Dean F. Bajorin, MD, explained that they are further subdivided into 3 main categories: metastatic bladder cancer, muscle-invasive bladder cancer (MIBC) without metastasis, and nonmuscle-invasive bladder cancer (ie, carcinoma in situ). The 3 types occur with different frequencies and require different management approaches.

Genomic studies like The Cancer Genome Atlas (TCGA) project have revealed numerous molecular subtypes and genetic signatures within the 3 main categories of bladder cancer.

 Bajorin said, “We know that there are a substantial number of mutations that we see in this disease. In fact, the mutation rate is right up there, with non—small cell lung cancer and melanoma.” He said the tumor’s genetic makeup appears to evolve over time. As a result, Bajorin said, metastatic bladder cancer has the highest prevalence of genetic mutations and “is poised for sensitivity to immune therapy.”

Elizabeth R. Plimack, MD, said multiple studies support a correlation between higher mutation load and greater likelihood of treatment response in bladder cancer. Plimack said she and colleagues investigated DNA repair genes in MIBC and found that “tumors with the highest number of alterations [had] the best response to cisplatin.”

 On the immunotherapy side, Rosenberg et al found that a higher mutational load predicted a good response to atezolizumab.

 Plimack said more data are needed to determine whether those likely to respond well to cisplatin and those likely to immunotherapy are the same people.

Patients with bladder cancer are also heterogeneous, and tend to be older. Bajorin said choice of treatment currently depends on the patient’s disease state and performance status. On one end, Bajorin said, “there are patients who are so-called good risk—that is, nodal-only disease, good performance status&mdash;and then at the other end of the spectrum are the patients who do very poorly, those who have visceral disease and have a poor performance status.”

“From a societal perspective, 10% to 15% of all bladder cancers in the United States don’t get treated at all,” said Robert Dreicer, MD. He said 1 reason many patients with advanced bladder cancer never receive treatment is because of tolerability issues with cisplatin, which forms the backbone of first-line chemotherapy. Thus, identifying a biomarker predictive of response to cisplatin would not render more patients eligible for chemotherapy.

David I. Quinn, MBBS, PhD, said everyone “would love a marker where we send it off [and] it comes back and says, ‘Look, this marker links to therapy X; please follow the dots,’” but he acknowledged that it is not that simple. “The disease state matters, as to whether the patient is eligible for chemotherapy as first-line,” he said

“Aggressive bladder cancers are challenging to treat and, until the recent availability of checkpoint inhibitors, patients with progression of metastatic disease platinum-based therapy had few options,” Petrylak said. The FDA approvals of all 5 PD-1/ PD-L1 checkpoint agents were based on positive clinical trial data. The panel discussed the safety and efficacy outcomes for each drug in detail.

Dreicer said that although only 20% to 25% of patients typically respond to the checkpoint inhibitors, he has observed responses in patients he typically would have referred to hospice. “Having these drugs is a paradigm shift,” he said.

Arjun V. Balar, MD, who was involved in several clinical trials for checkpoint inhibitors, said some of the outcomes were striking. According to Balar, a small percentage of patients in a firstline trial of atezolizumab had complete responses, and the median overall survival (OS) was a surprising 15.9 months.

“The impressive thing is the durability,” Petrylak said. He added that median duration of response has not been reached in several first- and secondline trials. Petrylak said although OS outcomes have been impressive, “progression-free survival is really fairly short with most of these studies— about 2 to 3 months.”

Plimack noted that PD-1/PD-L1 inhibitors appeared to have similar efficacy outcomes, with similar response rates and duration of response in the second-line trials. “They all interfere with the same pathway, and I think it shouldn’t be a surprise that we see some consistency of data across these data sets,” she said. “There’s very little, really, to differentiate them in terms of efficacy, in my view,” Plimack concluded

Most of the clinical trials analyzed whether PD-L1 expression predicts response to checkpoint inhibitors of PD-1/PD-L1, but Petrylak said results were inconsistent. Quinn said one reason for the conflicting data is because PD-L1 expression changes over time, whereas the studies obtain a snapshot of the tumor in time. He said that snapshot may have been collected “the day before we want to start therapy or within a week, or it could be from a cystectomy or nephroureterectomy that was done 7 years before, and they’re likely to be very different.” Balar said the IMvigor-210 trial of atezolizumab in advanced bladder cancer showed some correlation between PD-L1 expression and response.

He said approximately 28% of people who had the highest levels of PD-L1 expression responded to atezolizumab, compared with 8% to 10% of people who had the lowest level of PD-L1 expression. “Clearly, the message here is that even though there is a correlation with PD-L1 expression and response, having the lowest level of PD-L1 expression did not preclude response,” Balar said. He added that some PD-L1—negative patients had complete responses.

The panel seemed to agree that the data suggest some correlation between PD-L1 expression and outcomes but that PD-L1 was not likely to be the answer in the quest for a reliable biomarker to predict checkpoint inhibitor response. Several members expressed concern that PD-L1 expression could be used to deny patients access to a PD-1/ PD-L1 inhibitor.

Bajorin said between 5% and 10% of patients in clinical trials of checkpoint inhibitors develop immune-related adverse events (AEs). He said the most concerning toxicities are pneumonitis and colitis, which can have a subtle onset but progress quickly. “There are clear-cut paradigms for intervention in terms of grade of toxicity…and I would highly recommend that treating physicians really become very familiar with those,” he said. urothelial carcinoma.

Other frequent immune-related AEs are fatigue and hypothyroidism; less frequent ones are adrenal insufficiency and pan-hypopituitarism. Bajorin recommended that physicians maintain a heightened awareness of all the possible immune-related AEs. He also emphasized the need to educate patients thoroughly and repeatedly. “Our nurses speak with our patients about what to call in about. Even though it may seem subtle to them, we really want to know about it,” he said. urothelial carcinoma.

Balar said he has found it easier to predict which patients will have a difficult time with chemotherapy than with immunotherapy. Petrylak said it is critical to determine whether patients have any comorbid autoimmune disorders that a checkpoint inhibitor might exacerbate. urothelial carcinoma.

Although many checkpoint inhibitors are approved for melanoma and are being studied for urothelial carcinoma, Quinn cautioned against combining a CTLA-4 inhibitor approved for melanoma with a PD-1/PD-L1 inhibitor approved for urothelial carcinoma.

The explosion of new checkpoint immunotherapy drugs has changed the paradigm of care for patients with urothelial carcinoma, the most common form of bladder cancer.

Vol. 18/No. 14 | Oncology Live®

Prevention Program Targets Pancreatic Cancer Before It Gains a Foothold

Novel Therapy Partners Emerge in Melanoma Research

Epigenetic Assay Could Spare Patients From Additional Biopsies for Prostate Cancer

Myeloma Trial Explores Optimal Induction, Maintenance Regimens

Beyond Tumor Type: New Milestones on a Long Road

Experts Discuss Immunotherapy's Evolution in Bladder Cancer

Debate Over Randomized Trials: Necessary Versus Optional