We looked at the yield of pathogenic mutations identified in women diagnosed with endometrial cancer, and we found a few surprises. There are genes not traditionally associated with endometrial cancer that we found by doing broad panels.
—Dana Farengo-Clark, MS
The quality and quantity of original research presented at the National Comprehensive Cancer Network (NCCN) Annual Conference continue to grow since poster sessions debuted a few years ago. The ASCO Post offers summaries for just a few that caught our eye, out of more than 65 presented this year.
Active Surveillance for Small Renal Masses
For the management of renal cell carcinoma, active surveillance with delayed intervention appears to be a noninferior management strategy with regard to oncologic outcomes for well-selected patients with small renal masses. This finding came from a prospective multicenter trial led by Phillip M. Pierorazio, MD, of the James Buchanan Brady Urological Institute and Department of Urology at Johns Hopkins Medical Center, Baltimore.1
Most studies evaluating active surveillance for these tumors have been retrospective and “limited by selection and reporting bias,” according to the investigators.
In the current prospective multicenter study, the Delayed Intervention and Surveillance for Small Renal Masses (DISSRM) Registry was used to evaluate 497 patients with tumors ≤ 4 cm who chose intervention or active surveillance. Patients underwent imaging (computed tomography, magnetic resonance imaging, or ultrasound) at enrollment and every 4 to 6 months for 2 years, then every 6 to 12 months thereafter.
Patients with a tumor growth rate > 0.5 cm/year or tumor diameter > 4.0 cm (indicative of disease progression) were recommended for intervention, although a patient could choose delayed intervention at any time. Percutaneous renal biopsy was offered at enrollment and recommended when the growth rate exceeded 0.5 cm/yr.
The study enrolled 274 patients (55%) who elected primary intervention and 223 (45%) who selected active surveillance. Twenty-one patients (9.4%) crossed over to delayed intervention.
For the active surveillance patients, the growth rates and progression were as follows:
At a median follow-up of 2.1 years, 23 patients had died. Of 10 patients in the intervention group, 2 died of renal cell carcinoma; of 13 in the active surveillance group, none died of the disease.
The cancer-specific survival rate exceeded 99% in both arms. Five-year overall survival was 92% with primary intervention and 75% for active surveillance.
Two Paclitaxel Regimens Compared
In the treatment of breast cancer, dose-dense paclitaxel is often assumed to be more toxic than weekly paclitaxel, but investigators from Edwards Comprehensive Cancer Center in Huntington, West Virginia, reported that the regimens have a comparable tolerability profile.2
Mohamed Alsharedi, MD, suggested that some clinicians favor weekly paclitaxel because they deem the toxicities to be more than with dose-dense paclitaxel, based on the profile observed with weekly paclitaxel in the SWOG S0221 trial.3 To make treatment duration equal, however, SWOG S0221 tested six cycles of dose-dense paclitaxel, not four, which is the standard, he pointed out.
At the NCCN Conference, Dr. Alsharedi reported the results of a retrospective analysis of 121 patients treated with the two main paclitaxel regimens from 2008 to 2014 at his institution. “To our knowledge, there are no other data in the literature comparing the toxicities and tolerability between two commonly used standard-of-care paclitaxel-based regimens,” he said.
The comparison of these common paclitaxel schedules showed that 4 cycles of standard dose-dense paclitaxel was comparable to 12 weekly paclitaxel cycles in terms of toxicities and tolerability.
“Toxicity was comparable, even for the most concerning side effect, neuropathy,” Dr. Alsharedi said.
Grade 3/4 neuropathy occurred in 17% with dose-dense dosing and 18% with weekly dosing. Dose-dense dosing was associated with a significantly lower incidence of neutropenia grades 1/2 (10% vs 23%; P = .02) and a trend toward less grade 3/4 neutropenia (12% vs 24%; P = .07). Musculoskeletal adverse events, however, were higher with dose-dense dosing (71% vs 33%; P < .001).
The authors suggested that pegfilgrastim (Neulasta) is the most likely factor contributing to the lower incidence of neutropenia seen with dose-dense paclitaxel and could have contributed to the higher incidence of musculoskeletal toxicity. There was no significant difference in the need for dose reductions, treatment interruption, or drug discontinuation between the arms.
Dr. Alsharedi said the data can be used to inform patients that the two regimens are tolerable, with comparable toxicities. “We don’t want the oncologist to be biased in choosing weekly paclitaxel over dose-dense, based on toxicity,” he noted. “Patients can choose between these regimens, based on factors other than toxicity.”
Sentinel Node Positivity Rates by Hospital
In melanoma patients, positive rates for sentinel lymph node biopsy vary across hospitals. In low-volume hospitals, a lower-than-expected positivity rate is associated with decreased stage I survival, according to an analysis of 33,639 melanoma patients from 646 hospitals led by Christine V. Kinnier, MD, and Karl Y. Bilimoria, MD, MS, of the Northwestern Institute for Comparative Effectiveness Research in Oncology, Chicago.4
The researchers looked for the observed-to-expected ratios, dividing hospitals into terciles. The middle tercile of sentinel lymph node biopsy positivity is the desired range, thought to most accurately reflect optimal care.
Of the 33,639 patients, 2,918 (8.7%) had positive sentinel lymph nodes. Hospitals with the lowest volume of sentinel lymph node biopsies were the most likely to fall into “the extreme group,” ie, with more than 30% in the lowest positivity tercile, 30% in the highest, and only 17% in the ideal middle tercile range.
In contrast, in hospitals with the highest procedural volume, 30% fell into the middle positivity range. Hospitals falling mostly in the middle tercile also had the best overall survival rates at 5 years (90%).
“We found that the more [sentinel lymph node biopsies] you did for melanoma, the more likely you were to fall into the middle tercile for the observed-to-expected ratio of positive sentinel lymph node biopsies,” said Dr. Kinnier. If the hospital’s ratio is too low, the hospital may be missing true positive sentinel lymph node biopsies. If the hospital’s ratio is too high, the hospital may have a high number of false-positive sentinel lymph node biopsies, she indicated.
Dr. Kinnier suggested that, regardless of the number of lymph node biopsies performed annually, hospitals where few lymph node biopsies are performed annually might be expected to fall outside the middle tercile. However, high-volume hospitals with unfavorable rates might want to look for underlying reasons.
“We have suggested to the NCCN that this could be a process measure to use for quality reporting,” she said.
Endometrial Cancer Risk and Lynch Screening
Since endometrial cancer is part of the constellation of malignancies in Lynch syndrome, the current NCCN guidelines recommend that persons diagnosed with endometrial cancer before age 50 be screened for Lynch syndrome. The authors of a study reported at the NCCN Conference are suggesting that merely screening for Lynch syndrome does not go far enough in determining possible underlying genetic susceptibilities.5 Nearly 40% of the gene variants they found in their study were not traditionally associated with endometrial cancer, and the presence of pathogenic variants was similar in women over and under age 50.
The genetic risk of endometrial cancer has not been actively researched. Persons with Lynch syndrome have a 40% to 60% increased risk, while persons with mutations in PTEN and CHEK2 are at modestly increased risk. Genetic testing for women with endometrial cancer has focused primarily on mismatch repair genes, as 9% of cases diagnosed under age 50 will carry these mutations, but the role played by other cancer susceptibility genes is unknown.
“We looked at the yield of pathogenic mutations identified in women diagnosed with endometrial cancer, and we found a few surprises,” said Dana Farengo-Clark, MS, a certified genetics counselor at GeneDx in Gaithersburg, Maryland. “There are genes not traditionally associated with endometrial cancer that we found by doing broad panels.”
Researchers found that of 489 women with endometrial cancer, 56 (11.5%) harbored at least one pathogenic or likely pathogenic variant, and the frequency was similar for women ≤ 50 and > 50. Pathogenic/likely pathogenic mismatch repair gene variants accounted for most of the variants (92%) in the younger cohort, but they also were identified in 51% of those diagnosed over age 50. The analysis further showed:
The authors suggested that genetic testing via a multigene panel be considered for all women with a personal history of endometrial cancer who also report a family history of colon and/or breast cancer, regardless of their age at diagnosis, to increase the likelihood of clarifying an underlying hereditary predisposition. “We think we need a broader brush here,” Ms. Farengo-Clark commented.
Impact of Generic Imatinib
Imatinib (Gleevec) is expected to lose patent exclusivity in the near future. The entry into the marketplace of generic imatinib could significantly reduce health plan expenditures on tyrosine kinase inhibitor therapy and facilitate changes in class management by payers. Xcenda LLC and Bristol-Myers Squibb estimated the economic impact of the brand-name product’s loss of exclusivity and potential formulary management of requiring generic imatinib before use of a branded tyrosine kinase inhibitor.6
Xcenda’s Lisa Bloudek, PharmD, and colleagues used Truven Health MarketScan Commercial and Medicare Supplemental Data from patients with at least one claim for a tyrosine kinase inhibitor, stratifying patients by health plan type and patient age. The majority of patients received imatinib (69%), followed by dasatinib (Sprycel, 18%) and nilotinib (Tasigna, 12%).
They determined that the introduction of generic imatinib would result in a 29% reduction in tyrosine kinase inhibitor pharmacy spend, independent of additional formulary management, for both commercial and Medicare payers. The cumulative cost savings for a million-member plan over 2 years was estimated to be $6,840,427 and $22,952,646 for commercial and Medicare, respectively. The impact of formulary management, on the other hand, would be miniscule, with a cost savings of only 1% to 2%. ■
Disclosure: Dr. Pierorazio’s study was funded by an NCCN Young Investigators Award. Dr. Alsharedi reported no potential conflict of interest. Ms. Farengo-Clark and Dr. Kinnier reported no potential conflicts of interest. Dr. Bloudek reported that Bristol-Myers Squibb sponsored this work.
1. Pierorazio P, Trock BJ, Chang P, et al: Five-year analysis of multi-institutional prospective clinical trial of delayed intervention and surveillance for small renal masses: The DISSRM Registry. NCCN Annual Conference. Presented March 13, 2015.
2. Alsharedi M, Dotson J, Tirona M: Standard of care four doses of dose dense paclitaxel in the adjuvant treatment of breast cancer has equal toxicity profile to weekly paclitaxel. NCCN Annual Conference. Presented March 12, 2015.
3. Budd GT, Barlow WE, Moore HC, et al: SWOG S0221: A phase III trial comparing chemotherapy schedules in high-risk early-stage breast cancer. J Clin Oncol 33:58-64, 2015.
4. Kinnier C, Paruch JL, Dahlke AR, et al: Does hospital proficiency vary for melanoma sentinel lymph node biopsies? An evaluation of hospital level adjusted node positivity rates and outcomes. NCCN Annual Conference. Presented March 13, 2015.
5. Farengo-Clark D, Klein R, Marshall M, et al: Testing for inherited cancer pathogenic variants in women with endometrial cancer: Who to treat and for which genes to test? NCCN Annual Conference. Presented March 12, 2015.
6. Bloudek LM, Makenbaeva D, Eaddy M: Anticipated impact of generic imatinib market entry on tyrosine kinase inhibitor-related pharmacy costs. NCCN Annual Conference. Presented March 13, 2015.