In this edition of “How I Will Treat My Next Patient,” I review “guidelines for today” and speculate about “guidelines for tomorrow,” highlighting recommendations from the American Society of Clinical Oncology about hereditary cancer testing in epithelial ovarian cancer (OC) and data that support a reexamination of the age at which screening for colorectal cancer (CRC) should begin.
ASCO guidelines on genetic testing in epithelial ovarian cancer
Dr. Alan P. Lyss
After reviewing 19 studies, including 6 meta-analyses; 11 randomized, controlled trials; and 2 observational studies, an ASCO panel recommended germline genetic testing for BRCA1, BRCA2, and other ovarian cancer susceptibility genes for all women with newly diagnosed epithelial OC, regardless of family history (J Clin Oncol. 2020 Jan 27. doi: 10.1200/JCO.19.02960).
For OC patients with a germline mutation, cascade testing of first- and second-degree relatives was strongly urged. For patients without a germline mutation, the guidelines recommended offering somatic tumor testing for BRCA1/2 pathogenic or likely pathogenic variants at disease recurrence or after initial therapy and for mismatch repair deficiency (MMRD) in patients with clear cell, endometrioid, or mucinous and potentially other histologic types of OC. The authors cautioned that the discussion of testing results should involve professionals with expertise in the surveillance and management of hereditary cancer syndromes.
The panel said the discovery of germline or somatic pathogenic or likely pathogenic BRCA1/2 variants should lead to considering treatment with Food and Drug Administration–approved poly (ADP-ribose) polymerase inhibitors, including niraparib, olaparib, and rucaparib. Identification of MMRD in a patient with recurrent OC should trigger consideration of treatment with pembrolizumab, consistent with its labeled indications, and surveillance for other malignancies.
The guidelines cautioned that, when patients have variants of uncertain significance on germline testing, “clinical features and family history should inform clinical decision making.” Similarly, the panel made no recommendation regarding testing for or making treatment decisions based on tests for homologous recombination deficiency.
How these results influence practice
Every oncologist recognizes that better understanding of cancer biology can guide personalized diagnostic, predictive, prognostic, and therapeutic strategies for patients and their family members.
It is estimated that approximately 25% of all OC is caused by a heritable genetic condition. Germline mutations in BRCA1 and BRCA2 are identified in 13%-15% of patients with OC, and somatic mutations are found in an additional 7%. Perhaps 6% of all ovarian/fallopian tube/peritoneal cancers are caused by mutations in genes other than BRCA1/2. For that reason, germline sequencing should be performed via multigene panels that assess BRCA1/2 and other relevant mutations.
MMDR has been found in 10%-12% of unselected epithelial OC, with increased representation in nonserous histologies. That frequency is high enough to justify testing for it routinely.
Unfortunately, only about 30% of women undergo genetic testing. Given the frequency of molecular abnormalities in OC, this is problematic in every conceivable domain of clinical care for patients and family members. ASCO’s comprehensive, educational guidelines provide a template for shared decision making and utilize resources that are available in almost all clinical settings. For those clinicians who have recommended genetic testing for all epithelial OC patients, these guidelines are practice reaffirming. For the rest of us, they are practice changing.
Colorectal cancer cases spike after start of routine screening
Instead of examining CRC incidence by the usual 5- or 10-year age ranges, a group of researchers looked at CRC incidence in 1-year intervals for adults aged 30-60 years in the SEER-18 registry from 2000 to 2015 (JAMA Network Open. 2020 Jan 31. doi: 10.1001/jamanetworkopen.2019.20407). The researchers focused their attention on the transition between age 49 and 50 years, which is when routine screening generally begins and case-finding based on symptoms and signs of CRC alone ideally ends.
The group’s hypothesis was that steep increases in CRC incidence between ages 49 and 50 would be consistent with a high, undetected preclinical case burden in patients aged younger than 50 years and that this “real-world” registry data could help estimate outcomes of screening at younger ages. The researchers found that CRC incidence increased by 46.1% in the transition period from age 49 to 50 years. A majority (93%) of these cases were invasive and, therefore, likely to be clinically relevant. The increase in cancer rates occurred across geographical regions, gender, and race, and likely reflected the impact of screening. The states with the steepest increases in CRC between ages 49 and 50 (Connecticut and Utah) were the states with the first and third highest CRC screening rates for individuals 50 years of age and older.
Stage stratification showed steep increases in incidence in the target age range for localized and regional CRC and for colon and rectal tumors. In the transition between age 49 and 50, the researchers found a significant increase in 5-year relative survival (6.9% absolute increase, 10% relative increase), suggesting that earlier screening had a survival impact, apart from the effects of treatment in cases diagnosed after symptoms occurred.
The authors concluded that their analysis of the transition from age 49 to 50 years provides registry-based data regarding CRC risk among individuals younger than 50, which can add to existing modeling studies to help inform guidelines about the age at which to initiate screening.
How these results influence practice
Early-onset CRC (EOCRC) incidence is increasing, with controversy regarding whether average-risk screening should begin before age 50 years. The justification for starting screening at age 50 is that there is a near doubling of incidence from patients aged 45-49 years (34 per 100,000) to those aged 50-54 years (60.2 per 100,000).
However, the increase in CRC incidence beyond age 50 may not be because rates are truly lower among younger individuals but rather because of uneven screening between the two populations. Doubling times for CRCs have been estimated to be perhaps as long as 1,000 days. Because many CRCs are asymptomatic, observed incidence rates of EOCRC in SEER registries do not reflect preclinical CRC case burdens in younger patients.
The current interrogation of SEER-18 data to identify preexisting CRC that was clinically silent in the 1-year interval between age 49 and 50 is highly supportive of a large undiagnosed number of EOCRC cases. In SEER-18, CRC rates increased 46.1% in this 1-year age transition, more than in earlier 1-year age transitions. With almost 93% of cases being invasive, these data suggest a high case burden of preclinical, undetected, clinically relevant EOCRC in younger patients that is not reflected in observed SEER incidence rates examining wider age group intervals.
The dual goals of screening for CRC are to prevent malignant neoplasms by the removal of precancerous polyps and improve cancer-specific survival. The data presented suggest that, by starting average-risk screening at age 50 years, we may be “missing the window.” The 6.9% absolute and 10.1% relative survival increase in the target transition period suggest the authors’ hypothesis is correct.
As in any real-world database survey, the analysis is limited by a lack of specific outcomes data, the inability to determine when the cancers developed, and how long they germinated. Because of those limitations and others, more detailed studies are needed to determine the ideal age at which to begin CRC screening.
Modeling studies incorporating the steep incidence inflection point at 49-50 years can be conducted to estimate the incidence rate increase at, for example, 45 years; the cost-benefit ratio; quality-adjusted life-years gained; and other important endpoints. However, this review of over 170,000 cases of CRC, with a data-completeness rate of over 98%, over the 15-year time frame when CRC screening became common, supports a fresh look at whether it is within our power to improve outcomes for EOCRC patients by using existing technology but applying it earlier.
Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.