In 2015, when then President Barack Obama unveiled the country’s Precision Medicine Initiative in a State of the Union address, some $200 million was directed through the National Institutes of Health (NIH)1 to facilitate data-sharing and bring returns on this investment, including projects that would allow the collection of genetic samples in minority communities.

“Five years down the road, we’ve realized that there have been several challenges for a full-fledged implementation of the Precision Medicine Initiative, combined with the effective representative samples from multiple ethnic minorities,” said Kashyap Patel, MD, chief executive officer of Carolina Blood and Cancer Care Associates, based in Rock Hill, South Carolina. Patel is the current president of the Community Oncology Alliance (COA) and associate editor of Evidence-Based Oncology™.

Patel moderated a discussion, “Disparities in Cancer Care: Sources and Solutions,” which took place March 22, 2021. This was the first webcast of a new initiative by The American Journal of Managed Care®. This initiative, the Oncology Value Coalition, brings together experts in oncology care for online discussions in topics of interest.

Last fall, Patel said, a damning report came from the American Association for Cancer Research, when its assessment on disparities in cancer found the following (

34% of all deaths from cancer in those aged 25 to 74 could be prevented by 2035 if disparities in access to care were eliminated; and

from 2003 to 2006, disparities cost the nation $230 billion in direct medical costs, and indirect costs to society were more than $1 trillion.

“We have failed to address the core issue of bringing equity in access, to get access to research and access to testing,” Patel said.

Disparities in outcomes occur can arise from poverty or lack of transportation, said Karen Winkfield, MD, PhD, a radiation oncologist who last year became executive director of the Meharry-Vanderbilt Alliance in Nashville, Tennessee.

“There are many factors why minority patients may not be able to reach the doctor’s office, and then we blame them for the shortcomings that they have,” Patel said. “That’s beyond their control.”

Winkfield said access issues include testing. As a radiation oncologist, she has seen many patients with breast cancer. “And I cannot tell you how many times there would be a patient who had come, perhaps from an outside institution, who had a biopsy that was done, had their lumpectomy done, and they did not have Oncotype testing as part of that,” she said, referring to the 21-gene test that evaluates recurrence score.

The issue of disparities in cancer is multifactorial, as it can cover not only race, ethnic, and cultural issues, but also gender identif ication, said Debra Patt, MD, PhD, MBA, an Austin-based breast cancer specialist with Texas Oncology who is secretary of COA. Karen Winkfield, MD, PhD “Some issues are cultural and some are about trust. Some issues are socioeconomic and some are our exclusion criteria.”

Patt brought up a topic familiar to the whole panel: Medicaid access, or lack of it. Patel and Patt are based in states that have not expanded Medicaid, and Winkfield recently relocated from Wake Forest University in North Carolina, which is among them.

Black patients are more likely to have aggressive breast and prostate cancer and multiple myeloma, while Hispanic populations are likely to have higher rates of cervical and hepatobiliary cancers. But as a physician in 1 of 12 the states that have not expanded Medicaid, Patt said knows geography plays a role, too.

“We have a large portion of adult Texans who don’t have access to health care, period. And so, between ages 19 to 65, that’s about 25% of adults in Texas who don’t have access to insurance. We know in that patient population, that they’re 6 times more likely to present with advanced cancer, and they die more rapidly of their disease because they present with advanced cancer,” Patt said. “I think the access issue is a real hurdle that has to be overcome. We have to talk about it transparently because it factors into this.”

IMPLICATIONS OF UNDERSAMPLING MINORITY PATIENTS

Patel said minority groups also are underrepresented in genome-wide association studies that are used in drug development.

 According to a recent study, the degree to which they are underrepresented is astonishing: By 2017, of 35 million samples, 80% were of Northern European ancestry, even though this population is less than 10% of the population worldwide.

The implications are significant. “What shocks me is that when you look into the personalized medicine, we all are different biologically. So the starting point of the designer drug development process does not have information on who we are,” Patel said.

“Precision medicine has widened the gap to the point that patients of minority [groups] may live [shorter lives] compared to those who are represented in the drug development process,” Patel said. “How do we address that?”

As a breast cancer specialist, Patt sees how this happens up close: If the payer doesn’t cover the test, the test doesn’t happen. In metastatic breast cancer, that’s a lot of missed opportunity. Communicating the need for a test can be more challenging if there are economic and cultural barriers. “Is policy actually a coverage determination policy?” she asked. “I think if we could change those things that it would help.”

Patel spoke of the need to bring clinical trials to underserved areas and involve community oncologists to not only to reduce travel times for rural patients, but also to reduce the level of intimidation some may feel in dealing with an academic center. Winkfield, who earlier in her career was a clinical fellow at Harvard, said there are equally impressive examples of trials close to patients who live far from academic centers.

“There are great examples of community oncologists who are doing the good work of bringing clinical trials right into people’s backyard to make it better for them…to make it more accessible,” Winkfield said. Institutions and national organizations should look for ways to support this work, and she agreed with Patel that “it’s been a long time coming.”

Patt, who manages breast cancer trials for Texas Oncology, said there’s considerable administrative work to bring them to the community level, but it’s worth it. “We have 70 to 80 clinical trials at any given time, and it’s a lot of sweat equity,” she said. “It’s IVs every week and a lot of administrative time and support. But I think it’s really meaningful that community oncologists need to have this as a priority.”

The doctors agreed that more digitization of the administrative work would ease that burden and make trials more cost-effective. Winkfield noted that a “silver lining” of COVID-29 is that oncologypractices have learned they can do some administrative steps remotely, such as consents.

Is there opportunity for the Biden administration to expand Medicaid access to more patients, or can more be done to help oncology practices reduce disparities? The most obvious recent step is the new round of incentives in the American Rescue Plan of 2021 for the 12 states that have not expanded Medicaid. The panel discussed “carrots and sticks” that can be used in the drug approval process if manufacturers are not doing enough to enroll minority patients, and Winkfield noted the recent spate of withdrawn indications in lung and bladder cancer as a sign that FDA is enforcing requirements.

CMS can take an approach called coverage with evidence development, although attempts to do so in the area of chimeric antigen receptor T-cell therapy have been met with some pushback. Reducing disparities in cancer care has been a major agenda item for every major cancer group in the past year. Patel noted that the second part of the 21st Century Cures Act features an inclusivity mandate—meaning that drugs cannot be approved unless they will treat diverse populations. It will be up to the research community to help hold the pharmaceutical industry’s feet to the fire, he said.

The White House. Fact sheet: Obama administration announces key actions to accelerate Precision Medicine Initiative. February 25, 2016. Accessed March 29, 2021. https://obamawhitehouse.archives.gov/the-press-office/2016/02/25/fact-sheet-obama-administrationannounces-key-actions-accelerate

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McVeigh TP, Hughes LM, Miller N, et al. The impact of Oncotype DX testing on breast cancer management and chemotherapy prescribing patterns in a tertiary referral centre. Eur J Cancer. 2014;50(16):2763-2770. doi:10.1016/j.ejca.2014.08.002

Patel K, Patel M, Mukhi H. Despite advances in precision medicine, disparities persist. Targeted Therap Oncol. 2020;9(16): https://www.targetedonc.com/view/despite-advances-in-precision-medicinedisparities-persist

Cohn EG, Henderson GE, Appelbaum PS. Distributive justice, diversity and inclusion in precision medicine: what will success look like? Genet Med. 2017;19(2): 157-159. doi:10.1038/gim.2016.92

Geneviève LD, Martani A, Shaw D, Elger BS, Wangmo T. Structural racism in precision medicine: leaving no one behind. BMC Med Ethics. 2020;21(1):17. doi:10.1186/s12910-020-0457-8

Rosenbaum S, Handley M, Casoni M, Morris R. Medicaid and the American Rescue Plan: how it all fits together. Health Affairs blog. March 23, 2021. Accessed March 29, 2021. https://www.healthaffairs.org/do/10.1377/hblog20210322.860778/full/

McNulty R, Hagen A. FDA to reassess 6 oncology immunotherapy indications granted accelerated approval. The American Journal of Managed Care. March 12, 2021. Accessed March 28, 2021. 

https://www.ajmc.com/view/fda-to-reassess-6-oncology-immunotherapy-indications-grantedaccelerated-approval

Articles

The issue of disparities in cancer is multifactorial, as it can cover not only race, ethnic, and cultural issues, but also gender identification.

Multiple Factors Contribute to Disparities in Health and Cancer Outcomes 

A theme of the 2019 NCCN Annual Conference was the expansion of biomarker testing to guide treatment, and a review of brand-new changes for guidelines in colorectal cancer (CRC) was no different.

 Wells A. Messersmith, MD, co-director of the developmental therapeutics program at the University of Colorado Cancer Center, said work in this area is needed to fill the knowledge gaps in metastatic CRC, which has a 5-year survival rate of just 11%.

Complex genetics define metastatic CRC, which Messersmith said has 4 consensus subtypes, known as CMS1, CMS2, CMS3, and CMS4, with varying lengths of overall survival (OS).

Messersmith explained that while there are 13 FDA-approved drugs for CRC, until recently only 4 were biomarker-driven. The 2019 update adds treatment based on 

The cost of expensive combination therapy is driving the quest for better biomarkers, Messersmith explained, citing data from his university’s pharmacy that showed 24 to 30 months of combination therapy in metastatic  CRC exceeded $300,000 by 2013. At the same time, OS has increased incrementally. Spending more for better biomarker studies makes more sense than spending billions on therapies that don’t work or could be harmful, he said.

With that, he reviewed studies and key updates for 2019:

 an additional option was added for unresectable stage IV mCRC: mFOLFOXIRI plus the EGFR inhibitor panitumumab (Vectibix) for 

wild-type metastatic CRC were randomized in a 2:1 ratio to mFOLFOXIRI plus panitumumab (n = 63) or mFOLFOXIRI alone (n = 33). The objective response rate (ORR) with the addition of panitumumab was 85.7% compared with 54.5% with mFOLFOXIRI alone.

Although microsatellite instability (MSI) and mismatch repair (MMR) is usually not inherited, this does not rule out Lynch syndrome, which is seen in 1% of cancers with 

 Germline testing is indicated if there is a strong family history.

The latest guidelines also include additional explanation of MMR immunohistochemistry testing for the 4 genes known to be mutated in Lynch:

New frontline immunotherapy treatment options listed in the NCCN guidelines for advanced or metastatic CRC are nivolumab (Opdivo) or pembrolizumab (Keytruda), or a combination of nivolumab and ipilimumab (Yervoy), both in dMMR and MSI-H only. These recommendations are category 2B and are intended for patients who are not appropriate candidates for cytotoxic combination regimens. These same immunotherapy options are also listed in the guidelines as second- and third-line recommendations for dMMR/MSI-H patients.

Larotrectinib (Vitrakvi) is now a second-line treatment option

 gene fusion positive, based on a pivotal 2018 paper published in the 

The pivotal analysis was also the basis of the FDA’s November 2018 approval of larotrectinib for the treatment of adult and pediatric patients with solid tumors that have an 

gene fusion without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity, and have no satisfactory alternative treatments or that have progressed following treatment. The pivotal trial included 4 patients with CRC, 1 of whom achieved an objective response.

Combination therapies added to the guidelines as second-line options are: (1) dabrafenib (Tafinlar; 

), plus cetuximab or panitumumab (EGFR mAb), (2) encorafenib (Braftovi; BRAF) plus binimetinib (Mektovi; MEK) plus cetuximab or panitumumab (EGFR mAb).

The regimen of encorafenib/binimetinib and an EGFR inhibitor is supported by findings from the safety lead-in phase of the phase III BEACON trial. In 30 patients with 

 V600E-mutant metastatic CRC, the estimated median progression-free survival with encorafenib/binimetinib plus cetuximab was 8.0 months and the estimated median OS was 15.3 months with a median duration of follow-up of 18.2 months.

 The ORR was 48% by local assessment, with 3 patients achieving a complete response.

Messersmith WA. NCCN Guidelines Updates: Management of Metastatic Colorectal Cancer Presented at: 2019 NCCN Annual Conference; March 21-23, 2019; Orlando, FL.

Lenz HJ, Ou FS, Venook AP, et al. Impact of consensus molecular subtyping (CMS) on overall survival (OS) and progression free survival (PFS) in patients with metastatic colorectal cancer (mCRC): analysis of CALGB/SWOG 80405 (Alliance). 

. 2017;35(15 suppl):3511 DOI: 10.1200/JCO.2017.35.15_suppl.3511.

Geissler M, Riera-Knorrenschild J, Tannapfel A, et al. mFOLFOXIRI + panitumumab versus FOLFOXIRI as first-line treatment in patients with RAS wild- type metastatic colorectal cancer m(CRC): A randomized phase II VOLFI trial of the AIO (AIO- KRK0109). 

. 2018;36(15 suppl):3509. DOI: 10.1200/JCO.2018.36.15_suppl.3509.

Drilon A, Lactsch TW, Kummar S, et al. Efficacy of lacrotrectinib in TRK fusion—positive cancers in adults and children. 

. 2018;378:731-739. DOI: 10.1056/NEJMoa1714448.

Kopetz S, Grothey A, Yaeger R, et al. Updated results of the BEACON CRC safety lead-in: Encorafenib (ENCO) + binimetinib (BINI) + cetuximab (CETUX) for BRAFV600E-mutant metastatic colorectal cancer (mCRC). Presented at: 2019 Gastrointestinal Cancers Symposium; January 17-19; San Francisco, CA. Abstract 688.

A theme of the 2019 NCCN Annual Conference was the expansion of biomarker testing to guide treatment, and a review of brand-new changes for guidelines in colorectal cancer was no different.

Testing, Treatment Options Added to NCCN CRC Guidelines

PD-L1 testing, while an imperfect biomarker, is the key determinant of frontline immunotherapy selection in the NCCN guidelines for non—small cell lung cancer (NSCLC), reported Matthew A. Gubens, MD, at the 2019 NCCN Annual Meeting.

“PD-L1 testing is really the name of the game,” said Gubens, of the University of California at San Francisco Helen Diller Family Comprehensive Cancer Center. He explained that the KEYNOTE-024 trial showed that pembrolizumab (Keytruda) in patients with NSCLC more than doubled median overall survival (OS) compared with chemotherapy if PD-L1 expression was at least 50%, making that level an important cutoff point in treatment decisions. If PD-L1 expression is below 50%, treatment decisions turn on whether the cancer is squamous or nonsquamous.

Gubens also noted several guidelines that took effect in January 2019 combine pembrolizumab with chemotherapy. Although this brings greater toxicity, he said, clinicians and patients alike “will consider the higher disease burden with the idea that, ‘I want a response now, I may not get to second line.’”

In a comprehensive review at the NCCN meeting, Gubens discussed the significance of the 50% PD-L1 threshold, the role of disease histology, and the potential for additional biomarkers in the evolving NCCN guidelines for frontline immunotherapy in NSCLC.

Single-agent pembrolizumab is preferred as first-line therapy for NSCLC when PD-L1 expression is 50% or greater. This is a Category 1 guideline, which means there is uniform consensus that the intervention is appropriate. This guideline applies to both adenocarcinoma and squamous cell carcinoma, however, patients with 

 mutations should receive targeted agents, not immunotherapy, according to Gubens. The FDA approved pembrolizumab for this indication in October 2016.

The NCCN recommendation is based on the phase III KEYNOTE-024 trial, in which single-agent pembrolizumab more than doubled median OS compared with standard chemotherapy in patients with NSCLC and PD-L1 expression ≥50% whose tumors were not 

 positive. The median OS with the PD-1 inhibitor was 30.2 months versus 14.2 months with chemotherapy, representing a 37% reduction in the risk of death (hazard ratio, 0.63; 95% CI, 0.47-0.86; 

While single-agent pembrolizumab is the preferred Category 1 recommendation for frontline immunotherapy in patients with NSCLC and a PD-L1 level ≥50%, pembrolizumab- or atezolizumab (Tecentriq)-based chemoimmunotherapy regimens are also Category 1 recommendations that may be suitable for some patients. According to Gubens, factors to consider in potentially selecting these regimens include disease burden, symptom burden, and patient fitness. Several of these chemoimmunotherapy regimens are described in the next section, as they are the preferred options for patients with a PD-L1 level under 50%.

At this time, single-agent pembrolizumab is not recommended in the NCCN guidelines as a frontline treatment for patients with NSCLC and PD-L1 status <50%. The FDA is reviewing an application for pembrolizumab monotherapy for the frontline treatment of patients with locally advanced or metastatic nonsquamous or squamous non—small cell lung cancer (NSCLC) with a PD-L1 expression level of ≥1% and no 

The application is based on findings from the phase III KEYNOTE-042 trial, in which the median OS was 16.7 months with frontline pembrolizumab monotherapy compared with 12.1 months with standard chemotherapy in patients with advanced or metastatic NSCLC and PD-L1 ≥1% (HR, 0.81; 95% CI, 0.71-0.93; 

 Across all patients with PD-L1 status of 1% to 49%, which was an exploratory analysis, the median OS was 13.4 months with pembrolizumab compared with 12.1 months for chemotherapy (HR, 0.92; 95% CI, 0.77-1.11). The FDA is scheduled to make its decision on or before April 11, 2019.

For patients with nonsquamous advanced or metastatic NSCLC (ECOG performance status 0-1), and PD-L1 <50% the new NCCN guideline update added the regimen of pembrolizumab combined with pemetrexed (Alimta) and either cisplatin or carboplatin as a preferred Category 1 initial systemic therapy option (if no contraindications to adding pembrolizumab).

The recommendation is based on the phase III KEYNOTE-189 trial, in which patients were randomized 2:1 to receive pemetrexed and a platinum-based chemotherapy plus either pembrolizumab or placebo. Patients could cross over if they progressed on the control arm.

The results showed the addition of pembrolizumab to pemetrexed and either cisplatin or carboplatin in the first-line setting reduced the risk of death by 51% in patients with NSCLC without 

 The median OS was not reached with the pembrolizumab cohort compared with 11.3 months (95% CI, 8.7-15.1) in the chemotherapy-alone arm. At a median follow-up of 10.5 months, the estimated 12-month OS rate was 69.2% (95% CI, 64.1-73.8) in the pembrolizumab arm compared with 49.4% (95% CI, 42.1-56.2) in the control group (HR, 0.49; 95% CI, 0.38-0.64; 

While survival was more pronounced on those with 50% or greater PD-L1 expression, the pembrolizumab OS benefit was observed across PD-L1 subgroups, including the <1% expression group (12-month OS rate, 61.7% vs. 52.2%; HR, 0.59; 95% CI, 0.38-0.92); the 1% to 49% cohort (12-month OS rate, 71.5% vs. 50.9%; HR, 0.55; 95% CI, 0.34-0.90); and those with a score of 50% or greater (12-month OS rate, 73.0% vs. 48.1%; HR, 0.42; 95% CI, 0.26-0.68).

The KEYNOTE-189 trial was also the basis for the FDA granting a full approval to the pembrolizumab regimen in this setting in August 2018.

For patients with nonsquamous NSCLC who are not eligible to take pemetrexed, Gubens said the guidelines for frontline immunotherapy list atezolizumab combined with bevacizumab carboplatin, and paclitaxel (ABCP regimen) as a Category 1 recommendation. The FDA approved this regimen in December 2018.

The NCCN guideline update and FDA approval are based on findings from the phase III IMpower150 trial, in which the ABCP regimen reduced the risk of death by 22% compared with bevacizumab and chemotherapy (BCP) in patients with advanced wild-type NSCLC.

Additionally, the median OS with the addition of atezolizumab was 19.2 months (95% CI, 17.0-23.8) compared with 14.7 months (95% CI, 13.3-16.9) in the BCP arm (HR, 0.78; 95% CI, 0.64-0.96; 

 = .0164). The 24-month OS rate with atezolizumab was 43% compared with 34% for BCP. ABCP also improved median progression-free survival by 1.5 months compared with BCP (8.5 vs 7.0 months; HR, 0.71; 95% CI, 0.59-0.85; 

For patients with squamous NSCLC, the preferred Category 1 recommendation is for pembrolizumab in combination with carboplatin and either paclitaxel or nab-paclitaxel (Abraxane), which the FDA approved for this indication in October 2018. The approval and NCCN recommendation are based on the phase III KEYNOTE-407 trial.

In KEYNOTE-407, combining pembrolizumab with chemotherapy reduced the risk of death by 36% compared with chemotherapy alone in patients with metastatic squamous NSCLC.

 The median OS was 15.9 months (95% CI, 13.2 — not evaluable) with pembrolizumab versus 11.3 months (95% CI, 9.5-14.8) with chemotherapy alone (HR, 0.64; 95% CI, 0.49-0.85; 

 = .0017). The OS benefit was observed regardless of PD-L1 expression level, choice of taxane, age, sex, and ECOG performance status.

Gubens said as important as PD-L1 testing is now, this is the just the beginning. He covered the growing importance of understanding patients with high tumor mutation burden as a distinct population from those with high PD-L1 expression and said forthcoming blood assays could be promising in predicting which immunotherapies will work.

“In 5 years, PD-L1 might be archaic. Stay tuned for multidimensional and serial testing,” concluded Gubens, referring to tests that occur throughout cancer treatment, not just at the start.

Gubens MA. NCCN Guidelines Updates: New Immunotherapy Strategies for Improving Outcomes in Non-Small Cell Lung Cancer. Presented at: 2019 NCCN Annual Conference; March 21-23, 2019; Orlando, FL.

Brahmer JR, Rodríguez-Abreu D, Robinson AG, et al. Updated analysis of KEYNOTE-024: pembrolizumab vs platinum-based chemotherapy for advanced NSCLC with PD-L1 TPS ≥50%. Presented at: the IASLC 18th World Conference on Lung Cancer; October 15-18; Yokohama, Japan. Abstract OA 17.06 (ID 9582).

Lopes G, Wu YL, Kudaba I, et al. Pembrolizumab (pembro) versus platinum-based chemotherapy (chemo) as first-line therapy for advanced/metastatic NSCLC with a PD-L1 tumor proportion score (TPS) ≥ 1%: Open-label, phase 3 KEYNOTE-042 study. Presented at: 2018 ASCO Annual Meeting; June 1-5; Chicago. Abstract LBA4.

Gandhi L, Rodgríguez-Abreu D, Gadgeel S, et al. KEYNOTE-189: Randomized, double-blind, phase 3 study of pembrolizumab (pembro) or placebo plus pemetrexed (pem) and platinum as first-line therapy for metastatic NSCLC. Presented at 2018 AACR Annual Meeting; April 14-18, 2018; Chicago, Illinois. Abstract CT075.

Gandhi L, Rodgríguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus chemotherapy in metastatic non—small-cell lung cancer [published online April 16, 2018]. 

Socinski MA, Jotte R, Cappuzzo F, et al. Overall survival (OS) analysis of IMpower150, a randomized Ph 3 study of atezolizumab (atezo) chemotherapy (chemo) ± bevacizumab (bev) vs chemo + bev in 1L nonsquamous (NSQ) NSCLC. 

Socinski MA, Jotte R, Cappuzzo F, et al. Atezolizumab for First-Line Treatment of Metastatic Nonsquamous NSCLC. 

.Published online June 4, 2018. doi: 10.1056/NEJMoa1716948.

Paz-Ares LG, Luft A, Tafreshi A, et al. Phase 3 study of carboplatin-paclitaxel/nab-paclitaxel (Chemo) with or without pembrolizumab (Pembro) for patients (Pts) with metastatic squamous (Sq) non-small cell lung cancer (NSCLC). 

PD-L1 testing, while an imperfect biomarker, is the key determinant of frontline immunotherapy selection in the NCCN guidelines for non–small cell lung cancer.

PD-L1 Status Central to NCCN Update for Frontline NSCLC Immunotherapy

In recent years, pancreatic has passed breast cancer as the third leading cause of cancer death in the United States, and by 2030 it could be the leading cause, Margaret Tempero, MD, of the University of California San Francisco Helen Diller Family Comprehensive Cancer Center, said at the 2019 NCCN Annual Conference.

Many things about pancreatic cancer have not changed—it still lacks early symptoms and remains remarkably resistant to chemotherapy&mdash;but as Tempero shared at the NCCN meeting researchers are becoming savvier at pinpointing who is at risk. Her talk covered 3 areas that she said are important new additions to the NCCN guidelines:

 Germline testing should be considered for all pancreatic cancer patients.

Molecular analysis of tumors should be considered for patients with metastatic disease.

A new adjuvant therapy option increased survival in a recent study.

The foundation for treatment of metastatic pancreatic cancer is FOLFIRINOX (fluorouracil, leucovorin, irinotecan, and oxaliplatin), which Tempero said marked an advance nearly 10 years ago, but “It’s tough to take, and it’s tough for us to give.”

Clinicians have learned to make FOLFIRINOX tolerable—with strategies such as reduced doses of chemotherapy holidays. For some patients, gemcitabine plus nab-paclitaxel is an option. But the latest waves of progress have come by identifying familial syndromes, the associated genes, and the relative risk of pancreatic cancer, including the genes 

Tempero said work at Memorial Sloan Kettering Cancer Center offered germline testing (MSK IMPACT) to families for 76 to 88 cancer predisposition genes, along with genetic counseling.

 More than 10,000 people received tumor DNA sequencing, and 1040 were referred for germline analysis; 176 (16.9%) had genes associated with pancreatic cancer (only 42% of these would have been detected based on existing clinical guidelines).

Tempero said her own institution is doing germline testing. “We are astounded at what we are seeing,” she said. Most of the mutations are 

“Why does it matter? It matters a lot,” she said. ” It might give you therapeutic direction,” including whether a patient would be a candidate for a PARP inhibitor.

And, the knowledge matters to families. She said she doesn’t recommend screening for pancreatic cancer just based on a 

 mutation, but if a family member with this mutation develops pancreatic cancer, then screening would be recommended.

Tempero reviewed research presented in 2018 at the ASCO annual meeting from The Cancer Genome Atlas Project, which identified clinically relevant alterations in pancreatic cancer. The analysis of 150 specimens found 42% with 1 clinically relevant alteration, 25% with 2 or more alterations, and germline alterations in 8% of patients. The project paired alterations with 11 different therapies.

Tempero acknowledged that molecular profiling will not yield results for every patient, but when it does the results could be dramatic. “This is the needle in the haystack you want to find,” she said. One key going forward will be to take a different approach to collecting biopsy samples, so there is enough tissue for testing. “It’s going to change the way we do business,” Tempero said.

Treatments are starting to emerge for some of the molecular targets being identified. In February 2019, AstraZeneca and Merck (MSD), the codevelopers of olaparib (Lynparza), announced that findings from the phase III POLO trial showed that frontline maintenance therapy with the PARP inhibitor significantly reduced the risk of disease progression or death versus placebo in patients with germline 

-mutated metastatic adenocarcinoma of the pancreas. The companies plan to report the specific data from the trial at a future medical meeting.

Pembrolizumab (Keytruda) was approved in 2017 for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high or mismatch repair deficient (dMMR) solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options. The pivotal data that led to the approval included 6 patients with dMMR pancreatic cancers. Among this group 83% (n = 5) achieved a response to pembrolizumab.

Tempero said over a 30-year period of trying adjuvant therapy, “We haven’t been able to move the bar very much.” But in 2017, data from the ESPAC-4 trial showed that the combination of gemcitabine and capecitabine produced a median overall survival (OS) of 28 months, an increase of 5 months over previous results in resected pancreatic cancer.

The study randomized patients with resected pancreatic cancer to gemcitabine alone (n = 366) or in combination with capecitabine (n = 364). The median OS was 28.0 months with the combination versus 25.5 months with gemcitabine alone (HR, 0.82; 95% CI 0.68-0.98 ; 

Results subsequently presented at the 2018 ASCO Annual Meeting represented a milestone breakthrough in the adjuvant setting for pancreatic cancer. Findings from the PRODIGE 24/CCTG PA.6 study showed that the median OS was 54.4 months with modified FOLFIRINOX (mFOLFIRINOX) versus 35.0 months with gemcitabine.

 This translated to a 36% reduction in the risk of death (HR, 0.64; 95% CI, 0.48-0.86; 

After a median follow-up of 33.6 months, the median disease-free survival (DFS) was 21.6 months for the mFOLFIRINOX arm compared with 12.8 months in the gemcitabine group (HR, 0.58; 95% CI, 0.46-0.73; 

<.001). The 3-year DFS rates were 39.7% versus 21.4%, respectively.

There was also a recent setback in the adjuvant setting, with Celgene announcing that the adjuvant combination of nab-paclitaxel (Abraxane) and gemcitabine was not found to improve DFS compared with gemcitabine alone, as confirmed by independent radiological review, in patients with resected pancreatic cancer, according to topline findings of the phase III APACT trial. There was, however, an improvement in OS with the combination versus gemcitabine alone, reaching nominal statistical significance. Full findings will be presented at an upcoming medical meeting, according to Celgene.

Tempero MA. NCCN Guidelines Updates: Treatment of Pancreatic Cancer. Presented at: 2019 NCCN Annual Conference; March 21-23, 2019; Orlando, FL.

Mandelker D, Zhang L, Kemel Y, et al. Mutation Detection in Patients With Advanced Cancer by Universal Sequencing of Cancer-Related Genes in Tumor and Normal DNA vs Guideline-Based Germline Testing. 

. 2017;318(9):825-835. doi: 10.1001/jama.2017.11137.

Neoptolemos JP, Palmer DH, Ghaneh P, et al. Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. 

. 2017;389(10073):1011-1024. doi: 10.1016/S0140-6736(16)32409-6.

Conroy T, Hammel P, Hebbar M, et al; CCTG and the UNICANCER-GI/PRODIDGE Group. Unicancer GI PRODIGE 24/CCTG PA.6 trial: a multicenter international randomized phase III trial of adjuvant mFOLFIRINOX versus gemcitabine (gem) in patients with resected pancreatic ductal adenocarcinomas. Presented at: 2018 ASCO Annual Meeting; June 1-5, 2018; Chicago, IL. Abstract LBA4001. meetinglibrary.asco.org/record/159164/abstract.

In recent years, pancreatic has passed breast cancer as the third leading cause of cancer death in the United States, and by 2030 it could be the leading cause.

Germline Testing Emphasized in NCCN Guidelines on Pancreatic Cancer

New prostate cancer screening guidelines that seek to balance overtreatment concerns with the need to preserve gains in curbing prostate cancer mortality were unveiled at the National Comprehensive Cancer Network’s 19th Annual Conference, Advancing the Standard of Cancer Care, held March 14 in Hollywood, Florida.

Peter R. Carroll, MD, MPH, said the new guidelines, which call for starting screening as early as age 45 years and continuing it past age 70 years for patients in good health and without other comorbidities, would reduce overdetection by as much as 45%.

For 2 years, prostate cancer screening has been among the most contentious issues in cancer prevention. Since the development of the prostate-specific antigen (PSA) test, specialists promoted the screening tool among men and succeeded in trimming the prostate cancer mortality rate 45% in the United States-—a drop so steep it accounted for 20% of the overall drop in cancer mortality in men since 1930. An unqualified success, right?

Not according to the US Preventive Services Task Force (USPSTF), which in May 2012 stunned urologists and the cancer prevention community when it gave the PSA test a rating of D, saying that the benefits did not outweigh the harms. All that screening had led to overtreatment, USPSTF said. The entity’s recommendations are significant; only ratings of B or higher ensure reimbursement from Medicare and Medicaid, and private insurers often follow suit.

“We achieved a 45% reduction in mortality in prostate cancer in the United States, in contrast with an increase worldwide,” Dr Carroll said. “Yet, the USPSTF gives it a D.” “How did we arrive here?”

Both Carroll and his co-presenter, statistician Andrew J. Vickers, PhD, of Memorial Sloan Kettering Cancer Center said the USPSTF had some fundamental misunderstandings about the studies it relied upon in making its decision; Vickers in particular said the two studies, from the United States and Europe, were very different and numbers from each should not have been consolidated. But Carroll did agree with USPSTF on one point: Too much screening can lead to overtreatment.

The American Cancer Society did not agree with USPSTF; the American Urological Association responded with its own guidelines that targeted screening for men aged 55-69 years, although it was vague on when biopsies should occur.

That left the NCCN in a tough spot: The group dedicated to setting standards of care had weighed in on the matter just prior to the USPSTF edict in 2012 with a call for guidelines that Carroll described yesterday as “screen early, screen often, biopsy many.”

Carroll, who is professor and chair of the University of California, San Francisco Department of Urology, said the new guidelines will address the concerns of overtreatment as well as those of professional groups that want to preserve the use of PSA screenings. He said that the changes were being revised right up to the last minute; unlike other new material presented at the conference, these newsworthy guidelines were not included along with other electronic material provided to meeting attendees.

Carroll summarized the new criteria as follows:

		They define a target population based on more recent randomized, controlled trials.

		They seek testing that starts at age 45 to 50 years, with a single PSA test; later testing will be in selective patients based on risk factors.

		Indications for biopsy are more explicit and they will occur with caution: This is the biggest change in the guidelines. Only “highly suspicious” digital exams will be indicated for biopsy.

PSA velocity, by itself, will not be a reason for biopsy. Data will be published soon in support of these new criteria, Carroll said. He and Vickers agreed that the controversy over PSA testing will ebb as molecular profiling helps to resolve ambiguities around those moderate risk patients, for whom it has been a tougher call whether treatment or “watchful waiting” makes sense.

New prostate cancer screening guidelines that seek to balance overtreatment concerns with the need to preserve gains in curbing prostate cancer mortality were unveiled at the National Comprehensive Cancer Network's 19th Annual Conference.

Mary Caffrey

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