December 2018

Uterine Cancer Incidence and Mortality — United States, 1999–2016. Morbidity and Mortality Weekly Report (MMWR) https://www.cdc.gov/mmwr/volumes/67/wr/mm6748a1.htm?s_cid=mm6748a1_w

Sensitive tumour detection and classification using plasma cell-free DNA methylomes.  SY Shen, R Singhania, G Fehringer, A Chakravarthy, MHA Roehrl, D Chadwick, PC Zuzarte, A Borgida, TT Wang, TL, OK, Z Zhao, A Spreafico, T da Silva Medina, Y Wang, D Roulois, I Ettayebi, Z Chen, S Chow, T Murphy, A Arruda, GM O’Kane, J Liu, M Mansour, JD McPherson, C O’Brien, N Leighl, PL Bedard, N Fleshner, G Liu, MD Minden, S Gallinger, A Goldenberg, TJ Pugh, MM Hoffman, SV Bratman, RJ Hung & DD De Carvalho. Nature 563, pages579–583 (2018) Naturevolume 563, pages579–583 (2018) https://www.nature.com/articles/s41586-018-0703-0

The use of liquid biopsies for cancer detection and management is rapidly gaining prominence. Current methods for the detection of circulating tumour DNA involve sequencing somatic mutations using cell-free DNA, but the sensitivity of these methods may be low among patients with early-stage cancer given the limited number of recurrent mutations. By contrast, large-scale epigenetic alterations—which are tissue- and cancer-type specific—are not similarly constrained and therefore potentially have greater ability to detect and classify cancers in patients with early-stage disease. Here we develop a sensitive, immunoprecipitation-based protocol to analyse the methylome of small quantities of circulating cell-free DNA, and demonstrate the ability to detect large-scale DNA methylation changes that are enriched for tumour-specific patterns. We also demonstrate robust performance in cancer detection and classification across an extensive collection of plasma samples from several tumour types. This work sets the stage to establish biomarkers for the minimally invasive detection, interception and classification of early-stage cancers based on plasma cell-free DNA methylation patterns.

Genomic landscape and evolutionary trajectories of ovarian cancer early precursor lesions R‐C Wu,  P Wang,  S‐F Lin,  M Zhang,  Q Song,  T Chu,  BG Wang, RJ Kurman,  R Vang,  K Kinzler,  C Tomasetti,  Y Jiao,  I‐M Shih, TL Wang. Journal of Pathology https://doi.org/10.1002/path.5219  https://onlinelibrary.wiley.com/doi/pdf/10.1002/path.5219

The clonal relationship between ovarian high‐grade serous carcinoma (HGSC) and its presumed precursor lesion, serous tubal intraepithelial carcinoma (STIC), has been reported. However, when analyzing patients with concurrent ovarian carcinoma and tubal lesion, the extensive carcinoma tissues present at diagnosis may have effaced the natural habitat of precursor clone(s), obscuring tumor clonal evolutionary history, or may have disseminated to anatomically adjacent fimbriae ends, masquerading as precursor lesions. To circumvent these limitations, we analyzed the genomic landscape of incidental tubal precursor lesions including p53 signature, dormant STIC, or serous tubal intraepithelial lesion (STIL), and proliferative STIC in women without ovarian carcinoma or any cancer diagnosis using whole exome sequencing and amplicon sequencing. In three of the four cancer‐free women with multiple discrete tubal lesions, we observed non‐identical TP53 mutations between precursor lesions from the same individual. In one of the four women with co‐existing ovarian HGSC and tubal precursor lesion, we found non‐identical TP53 mutations and a lack of common mutations shared between her precursor lesion and carcinoma. Analyzing evolutionary history of multiple tubal lesions in the same four patients with concurrent ovarian carcinoma indicated distinct evolution trajectories. Collectively, the results support diverse clonal origins of tubal precursor lesions at the very early stages of tumorigenesis. Mathematical modeling based on lesion‐specific proliferation rates indicated that p53 signature and dormant STIC may take a prolonged time (two decades or more) to develop into STIC, whereas STIC may progress to carcinoma in a much shorter time (6 years). The above findings may have implications for future research aimed at prevention and early detection of ovarian cancer.

Causes of death among women with epithelial ovarian cancer by length of survival post-diagnosis: a population-based study in British Columbia, Canada. N Arora, A Talhouk, JN McAlpine, MR Law & GE Hanley. International Journal of Gynecologic Cancer http://dx.doi.org/10.1136/ijgc-2018-000040 https://ijgc.bmj.com/content/early/2018/12/20/ijgc-2018-000040

Objectives Little is known regarding the health of women who survive more than 5 years following their ovarian cancer diagnosis. To bridge an important gap in our knowledge about long term health of ovarian cancer survivors, we examined the causes of death among women diagnosed with epithelial ovarian cancer between 1990 and 2014 in British Columbia. These causes were stratified by years since diagnosis, and compared with age- standardized causes of death among women who have not been diagnosed with ovarian cancer.

Methods We examined all women with epithelial ovarian cancer in British Columbia 1990–2014 using population- based administrative datasets. We stratified women into three groups: all epithelial ovarian cancer patients; women surviving 5 to 9 years post-diagnosis, and women surviving 10 or more years since diagnosis. All- cause and cause specific standardized mortality ratios (SMRs) were calculated.

Results There were 4246 deaths among 6427 women with epithelial ovarian cancer. About 55.9% of deaths were from ovarian cancer. When compared with the general population, the highest SMRs (SMR of 5 or higher) were for deaths from other cancers and external causes (44.4% from falls) among women surviving 5–9 years and 10 or more years post-diagnosis. Mortality from other cancers can largely be explained by deaths from breast cancer (15.8%), lung cancer (12.3%), and colorectal cancer (11%).

Conclusions While the majority of epithelial ovarian cancer patients continue to die from their ovarian cancer, our results suggest that long term ovarian cancer survivors are particularly vulnerable to deaths from other cancers and from falls in elderly survivors. These data could indicate closer surveillance for breast, lung, and colorectal cancer, and closer attention to bone health is warranted among women surviving for 5 or more years following their epithelial ovarian cancer diagnosis.

Association of Nonadherence to Cancer Screening Examinations With Mortality From Unrelated Causes — A Secondary Analysis of the PLCO Cancer Screening Trial.  D Pierre-Victor, PF Pinsky.  JAMA Internal Medicine https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2719426

  • Question  Is nonadherence to medical tests, such as cancer screening, associated with mortality from unrelated causes?
  • Findings  In this secondary analysis of 64 567 participants in the Prostate, Lung, Colorectal and Ovarian Cancer Screening trial, higher unrelated mortality was observed among participants who were nonadherent to baseline cancer screening tests. Although trial participants were healthy volunteers, compared with fully adherent participants, nonadherent participants experienced higher rates of mortality from unrelated causes.
  • Meaning  A nonadherence behavior profile, marked by nonadherence to cancer screening tests, was associated with increased mortality among middle-aged and older adults.

Abstract

Importance  Patient nonadherence to chronic disease prevention guidelines is associated with increased mortality. Nonadherence to offered cancer screening tests may be associated with mortality among middle-aged and older adults.

Objective  To evaluate the association between nonadherence to cancer screening tests and mortality in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening trial, excluding mortality from cancers studied in the trial.

Design, Setting, and Participants  Randomization at 10 US screening centers occurred from November 8, 1993, to July 2, 2001. Original follow-up was through 13 years or December 31, 2009. Participants were re-consented to further follow-up starting May 18, 2011, and were observed until December 31, 2012. Protocol screening tests for the PLCO Cancer Screening trial intervention arm participants (N = 77 443) included chest radiographs and flexible sigmoidoscopy for both sexes, prostate-specific antigen tests and digital rectal examinations for men, and cancer antigen 125 tests and transvaginal ultrasonography for women. At baseline, participants completed a self-administered questionnaire. The cohort was classified into those receiving all sex-specified PLCO Cancer Screening trial screening tests at baseline (fully adherent), those receiving some but not all baseline tests (partially adherent), and those receiving no baseline tests (nonadherents). Secondary analysis was ad hoc in the original trial protocol. Statistical analysis was conducted from November 24, 2017, to August 29, 2018.

Main Outcomes and Measures  Mortality was ascertained via mailed annual study update questionnaires and searches of the National Death Index. Cox proportional hazards regression was used to analyze the association between mortality and adherence, controlling for various covariates.

Results  Of 77 443 participants in the intervention arm, 64 567 (29 537 women and 35 030 men; mean [SD] age, 62.3 [5.3] years) were included in the analysis based on consenting to trial participation before randomization and being eligible for all screening tests. Overall, 55 065 participants (85.3%) were adherent, 2548 (3.9%) were partially adherent, and 6954 (10.8%) were nonadherent with the baseline screening protocol. Within 10 years of follow-up, the hazard ratio of mortality, excluding deaths from cancers studied in the PLCO Cancer Screening trial and controlling only for age, sex, and race/ethnicity (model 1), was 1.73 (95% CI, 1.60-1.89) for nonadherent compared with fully adherent participants and 1.36 (95% CI, 1.19-1.54) for partially compared with fully adherent participants. After adjustment for medical risk factors for mortality and behavioral-related factors (model 2), the hazard ratio decreased to 1.46 (95% CI, 1.34-1.59) for nonadherent compared with fully adherent participants.

Conclusions and Relevance  Among participants in a screening trial for multiple cancers, a nonadherence behavior profile marked by nonadherence to protocol screenings was associated with higher overall mortality (excluding deaths from cancers studied in the trial). The generalizability of this finding to routine clinical practice should be assessed.

Possibility: flawed recruitment and randomization in the PLCO.

Methylomic Analysis of Ovarian Cancers Identifies Tumor-Specific Alterations Readily Detectable in Early Precursor Lesions.  TR. Pisanic II, LM Cope, S-F Lin, T-T Yen, P Athamanolap, R Asaka, K Nakayama, AN Fader, Ta-H Wang, I-M Shih and T-L Wang.  DOI: 10.1158/1078-0432.CCR-18-1199 Clinical Cancer Res December 2018 vol 24 (24).

Purpose: High-grade serous ovarian carcinoma (HGSOC) typically remains undiagnosed until advanced stages when peritoneal dissemination has already occurred. Here, we sought to identify HGSOC-specific alterations in DNA methylation and assess their potential to provide sensitive and specific detection of HGSOC at its earliest stages.

Experimental Design: MethylationEPIC genome-wide methylation analysis was performed on a discovery cohort comprising 23 HGSOC, 37 non-HGSOC malignant, and 36 histologically unremarkable gynecologic tissue samples. The resulting data were processed using selective bioinformatic criteria to identify regions of high-confidence HGSOC-specific differential methylation. Quantitative methylation-specific real-time PCR (qMSP) assays were then developed for 8 of the top-performing regions and analytically validated in a cohort of 90 tissue samples. Lastly, qMSP assays were used to assess and compare methylation in 30 laser-capture microdissected (LCM) fallopian tube epithelia samples obtained from cancer-free and serous tubal intraepithelial carcinoma (STIC) positive women.

Results: Bioinformatic selection identified 91 regions of robust, HGSOC-specific hypermethylation, 23 of which exhibited an area under the receiver-operator curve (AUC) value ≥ 0.9 in the discovery cohort. Seven of 8 top-performing regions demonstrated AUC values between 0.838 and 0.968 when analytically validated by qMSP in a 90-patient cohort. A panel of the 3 top-performing genes (c17orf64, IRX2, and TUBB6) was able to perfectly discriminate HGSOC (AUC 1.0). Hypermethylation within these loci was found exclusively in LCM fallopian tube epithelia from women with STIC lesions, but not in cancer-free fallopian tubes.

Conclusions: A panel of methylation biomarkers can be used to accurately identify HGSOC, even at precursor stages of the disease.

Association of Analgesic Use With Risk of Ovarian Cancer in the Nurses’ Health Studies.  ME Barnard, EM Poole, GC Curhan.  JAMA Oncol. 2018;4(12):1675-1682. doi:10.1001/jamaoncol.2018.4149. https://jamanetwork.com/journals/jamaoncology/article-abstract/2704211

  • Question  Are findings from case-control studies that report lower ovarian cancer risk among low-dose aspirin users reproducible in a large prospective study?
  • Findings  This cohort study using data from the Nurses’ Health Study and Nurses’ Health Study II observed a 23% lower risk of ovarian cancer among current low-dose aspirin users compared with nonusers. However, current use of nonaspirin nonsteroidal anti-inflammatory drugs was associated with a 19% higher risk of ovarian cancer compared with nonuse, and positive trends were observed for duration and cumulative average tablets per week.
  • Meaning  These results support a lower risk of ovarian cancer among low-dose aspirin users, although the association between other nonsteroidal anti-inflammatory drugs and ovarian cancer may be more complex.

Abstract

Importance  Ovarian cancer is a highly fatal malignant neoplasm with few modifiable risk factors. Case-control studies have reported a modest reduced risk of ovarian cancer among women who frequently use aspirin or regularly use low-dose aspirin.

Objective  To evaluate whether regular aspirin or nonaspirin nonsteroidal anti-inflammatory drug (NSAID) use and patterns of use are associated with lower ovarian cancer risk.

Design, Setting, and Participants  This cohort study analyzed NSAID use and ovarian cancer diagnosis data from 2 prospective cohorts, 93 664 women in the Nurses’ Health Study (NHS), who were followed up from 1980 to 2014, and 111 834 in the Nurses’ Health Study II (NHSII), who were followed up from 1989 to 2015. Follow-up was completed on June 30, 2014, for the NHS and June 30, 2015, for NHSII. Data were analyzed from June 13, 2016, to September 18, 2017.

Exposures  For each analgesic type (aspirin, low-dose aspirin, nonaspirin NSAIDs, and acetaminophen), timing, duration, frequency, and number of tablets used were evaluated; exposure information was updated every 2 to 4 years.

Main Outcomes and Measures  Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% CIs for associations of aspirin, nonaspirin NSAIDs, and acetaminophen with risk of epithelial ovarian cancer. All statistical tests were 2-sided, with a significance level of .05.

Results  In the NHS, the mean (SD) age at baseline (1980) was 45.9 (7.2) years, and 93% of participants identified as non-Hispanic white. In the NHSII, the mean age at baseline (1989) was 34.2 (4.7) years, and 92% identified as non-Hispanic white. Among the 205 498 women in both cohorts, there were 1054 cases of incident epithelial ovarian cancer. Significant associations between aspirin and ovarian cancer risk were not observed when current vs nonuse of any aspirin was evaluated regardless of dose (HR, 0.99; 95% CI, 0.83-1.19). However, when low-dose (≤100-mg) and standard-dose (325-mg) aspirin were evaluated separately, an inverse association for low-dose aspirin (HR, 0.77; 95% CI, 0.61-0.96), but no association for standard-dose aspirin (HR, 1.17; 95% CI, 0.92-1.49) was observed. Current use of nonaspirin NSAIDs was positively associated with risk of ovarian cancer compared with nonuse (HR, 1.19; 95% CI, 1.00-1.41), and significant positive trends for duration of use (P = .02 for trend) and cumulative average tablets per week (P = .03 for trend) were observed. There were no clear associations for the use of acetaminophen.

Conclusions and Relevance  These results appear to be consistent with case-control studies that show a reduced risk of ovarian cancer among regular users of low-dose aspirin. An increased risk of ovarian cancer with long-term high-quantity use of other analgesics, particularly nonaspirin NSAIDs, was observed, although this finding requires confirmation.

Neoadjuvant chemotherapy versus debulking surgery in advanced tubo-ovarian cancers: pooled analysis of individual patient data from the EORTC 55971 and CHORUS trials.  I Vergote, C Coens, M Nankivell, GB Kristensen, MKB Parmar, T Ehlen, GC Jayson, N Johnson, AM Swart, R Verheijen, WG McCluggage, T Perren, P Panici, G Kenter, A Casado, C Mendiola, G Stuart, NS Reed & S Kehoe.  Lancet Oncology, The, 2018-12-01, Volume 19, Issue 12, Pages 1680-1687.  https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30566-7/fulltext

Background  Individual patient data from two randomised trials comparing neoadjuvant chemotherapy with upfront debulking surgery in advanced tubo-ovarian cancer were analysed to examine long-term outcomes for patients and to identify any preferable therapeutic approaches for subgroup populations.

Methods  We did a per-protocol pooled analysis of individual patient data from the European Organisation for Research and Treatment of Cancer (EORTC) 55971 trial ( NCT00003636 ) and the Medical Research Council Chemotherapy Or Upfront Surgery (CHORUS) trial (ISRCTN74802813). In the EORTC trial, eligible women had biopsy-proven International Federation of Gynecology and Obstetrics (FIGO) stage IIIC or IV invasive epithelial tubo-ovarian carcinoma. In the CHORUS trial, inclusion criteria were similar to those of the EORTC trial, and women with apparent FIGO stage IIIA and IIIB disease were also eligible. The main aim of the pooled analysis was to show non-inferiority in overall survival with neoadjuvant chemotherapy compared with upfront debulking surgery, using the reverse Kaplan-Meier method. Tests for heterogeneity were based on Cochran’s Q heterogeneity statistic.

Findings  Data for 1220 women were included in the pooled analysis, 670 from the EORTC trial and 550 from the CHORUS trial. 612 women were randomly allocated to receive upfront debulking surgery and 608 to receive neoadjuvant chemotherapy. Median follow-up was 7·6 years (IQR 6·0–9·6; EORTC, 9·2 years [IQR 7·3–10·4]; CHORUS, 5·9 years [IQR 4·3–7·4]). Median age was 63 years (IQR 56–71) and median size of the largest metastatic tumour at diagnosis was 8 cm (IQR 4·8–13·0). 55 (5%) women had FIGO stage II–IIIB disease, 831 (68%) had stage IIIC disease, and 230 (19%) had stage IV disease, with staging data missing for 104 (9%) women. In the entire population, no difference in median overall survival was noted between patients who underwent neoadjuvant chemotherapy and upfront debulking surgery (27·6 months [IQR 14·1–51·3] and 26·9 months [12·7–50·1], respectively; hazard ratio [HR] 0·97, 95% CI 0·86–1·09; p=0·586). Median overall survival for EORTC and CHORUS patients was significantly different at 30·2 months (IQR 15·7–53·7) and 23·6 months (10·5–46·9), respectively (HR 1·20, 95% CI 1·06–1·36; p=0·004), but was not heterogeneous (Cochran’s Q, p=0·17). Women with stage IV disease had significantly better outcomes with neoadjuvant chemotherapy compared with upfront debulking surgery (median overall survival 24·3 months [IQR 14·1–47·6] and 21·2 months [10·0–36·4], respectively; HR 0·76, 95% CI 0·58–1·00; p=0·048; median progression-free survival 10·6 months [7·9–15·0] and 9·7 months [5·2–13·2], respectively; HR 0·77, 95% CI 0·59–1·00; p=0·049).

Interpretation  Long-term follow-up data substantiate previous results showing that neoadjuvant chemotherapy and upfront debulking surgery result in similar overall survival in advanced tubo-ovarian cancer, with better survival in women with stage IV disease with neoadjuvant chemotherapy. This pooled analysis, with long-term follow-up, shows that neoadjuvant chemotherapy is a valuable treatment option for patients with stage IIIC–IV tubo-ovarian cancer, particularly in patients with a high tumour burden at presentation or poor performance status.

COMPREHENSIVE REVIEW: Development of PARP and Immune-Checkpoint Inhibitor Combinations. RA Stewart, PG Pilié & Timothy A Yap. Cancer Res 78 (24) ; 6717-6725. DOI: 10.1158/0008-5472.CAN-18-2652

http://cancerres.aacrjournals.org/content/78/24/6717

A preoperative risk score to predict red blood cell transfusion in patients undergoing hysterectomy for ovarian cancer. 

SA Ackroyd, J Brown, K Houck, C Chu, G Mantia-Smaldone, S Rubin & E Hernandez. American Journal of Obstetrics and Gynecology Volume 219, Issue 6.  https://www.ajog.org/article/S0002-9378(18)30759-2/pdf

Background  Patients with ovarian cancer experience a high rate of anemia throughout their treatment course, with rates that range from 19–95%. Blood transfusions offer symptom relief but may be costly, are limited in supply, and have been associated with worse 30-day surgical morbidity and mortality rates.

Objective  The purpose of this study was to identify risk factors for blood transfusion with packed red blood cell and to develop a transfusion risk score to identify patients who undergo surgery for ovarian cancer and who are at lowest risk for a blood transfusion. Our aim was to help clinicians identify those patients who may not require a crossmatch to encourage resource use and cost-savings.

Study Design  This is a retrospective database cohort study of 3470 patients who underwent hysterectomy for ovarian cancer with the use the National Surgical Quality Improvement Program database from 2014–2016. The association between risk factors with respect to 30-day postoperative blood transfusion was modeled with the use of logistic regression. A risk score to predict blood transfusion was created.

Results  Eight hundred ninety-one (25.7%) patients received a blood transfusion. In multivariate analysis, blood transfusion was associated independently with age (odds ratio, 1.90, P <.01), African American race (odds ratio, 2.30; P <.01), ascites (odds ratio, 1.89; P =.02), preoperative hematocrit level <30% (odds ratio, 10.70; P <.01), preoperative platelet count >400×10 9 /L (odds ratio, 1.75; P <.01), occurrence of disseminated cancer (odds ratio, 1.71; P <.01), open surgical approach (odds ratio, 7.88; P <.01), operative time >3 hours (odds ratio, 2.19; P <.01), and additional surgical procedures that included large bowel resection (odds ratio, 4.23; P <.01), bladder/ureter resection (odds ratio, 1.69; P =.02), and pelvic exenteration ( P =.02). A preoperative risk score that used age, race, ascites, preoperative hematocrit level, platelets, presence of disseminated cancer, planned hysterectomy approach, and procedures accurately predicted blood transfusion with good discriminatory ability (C-statistic=0.80 [ P <.001]; C-statistic=0.69 [ P <.001] for derivation and validation datasets, respectively) and calibration (Hosmer-Lemeshow goodness-of-fit, P =.081; P =.56 for derivation and validation datasets, respectively).

Conclusion  Patients who undergo hysterectomy for ovarian cancer experience a high incidence of blood transfusions in the perioperative period. Preoperative risk factors and planned surgical procedures can be used in our transfusion risk score to help predict anticipated blood requirements.

Progress in BRCA-Mutated Ovarian Cancer.  DR Spriggs & DL Longo.  N Engl J Med 2018; 379:2567-2568 DOI: 10.1056/NEJMe1812644.

The article by Moore et al. in  NEJM is the culmination of a long march for olaparib in the treatment of BRCA-mutated high-grade serous ovarian cancer — one that began with its discovery by means of synthetic lethality screening, followed by years of clinical trials to define its activity and refine its uses, and finally led to its implementation in a population of women with potentially curable ovarian cancer. Olaparib is the first in a wave of poly(adenosine diphosphate–ribose) polymerase (PARP) inhibitors, a class of agents that is changing primary treatment of ovarian cancer for the first time in a generation.

Nearly all the patients in the SOLO1 trial had a germline mutation in BRCA1 or BRCA2 (BRCA1/2), and the results may not be generalizable to patients with either somatic BRCA mutations or wild-type BRCA genes. The patients were having a partial or complete response to a platinum-based chemotherapy regimen at the time that they were randomly assigned to receive either oral olaparib maintenance therapy or placebo. After 3 years, the percentage of patients who were alive and free from disease progression was 60% in the olaparib group, as compared with 27% in the placebo group (hazard ratio for disease progression or death, 0.30), with a 70% decrease in the risk of cancer recurrence or death with olaparib.

There were very real toxic effects, primarily related to the myelosuppression that so commonly occurs with cancer treatments, and less than 50% of the patients in the olaparib group completed the 2-year treatment plan. Additional studies will be needed to evaluate the effect of PARP inhibitors in other, less susceptible populations, including patients who have other defects in the repair of double-stranded DNA breaks, somatic (tumor) BRCA1 mutations, epigenetically silenced BRCA1/2 expression, or even intact BRCA1/2 function in the context of ovarian cancer. This trial did not include any of these groups.

At least two essential questions remain about the use of PARP inhibitors in patients with high-grade serous ovarian cancer. First, will the dramatic improvement in progression-free survival translate to an overall survival benefit or even an improved cure rate? Our previous experience with other maintenance treatments for ovarian cancer has been disappointing. Extended monthly paclitaxel therapy had a limited effect and was never adopted by the oncology community. Bevacizumab maintenance therapy showed a less promising progression-free survival benefit than olaparib and did not show a consistent survival benefit. On the basis of the mechanism of PARP inhibitors, it is reasonable to hope that this treatment will lead to prolonged survival in women with ovarian cancer, and we look forward to scientific proof of that improvement.

The second question is related to long-term toxic effects. Could long-term use of agents that interfere with repair of double-stranded DNA breaks result in the development of the myelodysplastic syndrome and acute leukemia? So far, across the PARP inhibitor class, accumulating evidence suggests that the risk of these effects is quite low (<2%), but longer-term follow-up is essential to answer this question.

Implicit in the successful trial by Moore et al. is an unresolved problem in precision oncology. The patients who were enrolled in the trial had “a deleterious or suspected deleterious germline or somatic BRCA1/2 mutation.” Thus, the generalizability of the results of this trial to other populations depends on the definition of “deleterious mutation.”

BRCA1 and BRCA2 founder mutations, which were originally identified in the Ashkenazi Jewish population, are generally understood to have deleterious effects. However, the BRCA1/2 genes are very large, and it is not unusual to find nonpathogenic sequence variations in these genes. The complexity arises in the presence of rare variants that have uncertain behavior and are not assigned to the pathogenic group or the nonpathogenic group. These variants may or may not have adverse effects on the function of BRCA1 and BRCA2 gene products. Known as “variants of unknown significance,” these variants do not fall under the binary designation of functional or nonfunctional.  The ability to assign a clinical effect to these variants is at the cutting edge of personalized medicine. The algorithms that are used for assignment depend on the depth of the database, maintained according to sequencing entity, and the detail of clinical correlation. Variants of unknown significance may be classified as favorable, unfavorable, or uncertain by the different algorithms. Different classifications may put the patient at risk for inappropriate treatment.  There are growing efforts to form expert consensus through the creation of public sharing platforms — such as ClinVar, ClinGen, and the Clinical Working Group of ENIGMA (Evidence-based Network for the Interpretation of Germline Mutant Alleles) — that collate the knowledge regarding genetic variants.5-7 Not all providers of genetic sequencing currently participate in these platforms. In the SOLO1 trial, the proprietary BRACAnalysis test by Myriad was used to screen patients for enrollment in the trial, and Myriad has chosen not to participate in any of these public platforms.  Despite a request from the Journal, Myriad has declined to provide the actual identity and distribution of the genetic variants detected in the patients in this trial for review or publication. They insist on keeping relevant patient data secret. It is truly disappointing that Myriad has placed its quest for riches ahead of the patients who might benefit from the generosity of the many patients who have freely provided Myriad with their data.  It is likely that only a few patients with controversial variants were included in the SOLO1 trial and that the effect of these variants did not alter the reliability of the results. It is possible, however, that some patients had rare genetic variants of unknown significance that might be classified differently by a different system. When the results of the trial are applied in practice, the trial treatment might be incorrectly excluded from or included in regimens for patients with those and other rare variants. Given that the knowledge of genetic variants is dynamic and additional specific adverse variants will certainly be discovered, full transparency by reporting to ClinGen or similar sources would be a helpful requirement in the future, so that patients with BRCA1/2 mutations can fully benefit from the sacrifices of the participants in the trial.

Maintenance Olaparib in Patients with Newly Diagnosed Advanced Ovarian Cancer

K Moore, N Colombo, G Scambia, B-G Kim, A Oaknin, M Friedlander, A Lisyanskaya, A Floquet, A Leary, GS. Sonke, C Gourley, S Banerjee, A Oza, A González-Martín, C Aghajanian, W Bradley, C Mathews, J Liu, ES Lowe, R Bloomfield, P DiSilvestro. N Engl J Med 2018; 379:2495-2505 DOI: 10.1056/NEJMoa1810858  https://www.nejm.org/doi/full/10.1056/NEJMoa1810858

BACKGROUND  Most women with newly diagnosed advanced ovarian cancer have a relapse within 3 years after standard treatment with surgery and platinum-based chemotherapy. The benefit of the oral poly(adenosine diphosphate–ribose) polymerase inhibitor olaparib in relapsed disease has been well established, but the benefit of olaparib as maintenance therapy in newly diagnosed disease is uncertain.

METHODS  We conducted an international, randomized, double-blind, phase 3 trial to evaluate the efficacy of olaparib as maintenance therapy in patients with newly diagnosed advanced (International Federation of Gynecology and Obstetrics stage III or IV) high-grade serous or endometrioid ovarian cancer, primary peritoneal cancer, or fallopian-tube cancer (or a combination thereof) with a mutation in BRCA1, BRCA2, or both (BRCA1/2) who had a complete or partial clinical response after platinum-based chemotherapy. The patients were randomly assigned, in a 2:1 ratio, to receive olaparib tablets (300 mg twice daily) or placebo. The primary end point was progression-free survival.

RESULTS  Of the 391 patients who underwent randomization, 260 were assigned to receive olaparib and 131 to receive placebo. A total of 388 patients had a centrally confirmed germline BRCA1/2 mutation, and 2 patients had a centrally confirmed somatic BRCA1/2 mutation. After a median follow-up of 41 months, the risk of disease progression or death was 70% lower with olaparib than with placebo (Kaplan–Meier estimate of the rate of freedom from disease progression and from death at 3 years, 60% vs. 27%; hazard ratio for disease progression or death, 0.30; 95% confidence interval, 0.23 to 0.41; P<0.001). Adverse events were consistent with the known toxic effects of olaparib.

CONCLUSIONS  The use of maintenance therapy with olaparib provided a substantial benefit with regard to progression-free survival among women with newly diagnosed advanced ovarian cancer and a BRCA1/2 mutation, with a 70% lower risk of disease progression or death with olaparib than with placebo.

Role of Screening History in Clinical Meaning and Optimal Management of Positive Cervical Screening Results PE Castle,  WK Kinney,  X Xue,  LC Cheung,  JC Gage, NE Poitras,  TS Lorey,  HA Katki,  N Wentzensen, M Schiffman, JNCI:  djy192,  https://academic.oup.com/jnci/advance-article-abstract/doi/10.1093/jnci/djy192/5256991?redirectedFrom=fulltext  

Background  Cervical cancer is caused by persistent human papillomavirus (HPV) infection. US consensus management guidelines for a positive cervical screening result typically focus on the current screening result only. A negative testing history may alter risk of the following positive screening results, caused by a new HPV infection, and therefore its optimal management.

Methods  Women ages 30 years and older were screened with triennial HPV and cytology co-testing at Kaiser Permanente Northern California from 2003 to 2014. We estimated the subsequent 5-year risks of cervical intraepithelial neoplasia grade 3 or more severe diagnoses (CIN3+) in a cohort of 1 156 387 women following abnormal (atypical squamous cells of undetermined significance [ASC-US] or worse) cytology and/or positive HPV testing, when the test result followed 0 (n = 990 013), 1 (n = 543 986), 2 (n = 245 974), or 3 (n = 79 946) consecutive negative co-test(s). All statistical tests were two-sided.

Results  Following 0–3 successive negative co-tests, 5-year CIN3+ risks following a positive HPV test decreased progressively from 7.2% (95% CI = 7.0% to 7.4%) to 1.5% (95% CI = 0.7% to 3.4%) (Ptrend < .001). Similarly, risks following an abnormal (ASC-US or worse) cytology result decreased from 6.6% (95% CI = 6.4% to 6.9%) to 1.1% (95% CI = 0.5% to 2.3%) (Ptrend < .001). Risks following low-grade squamous intraepithelial lesion, the risk threshold for referral to colposcopy in the United States, decreased from 5.2% (95% CI = 4.7% to 5.7%) to 0.9% (95% CI = 0.2% to 4.3%). Risks following high-grade squamous intraepithelial lesion or more severe, a specific marker for the presence of precancerous lesions, decreased from 50.0% (95% CI = 47.5% to 52.5%) to 10.0% (95% CI = 2.6% to 34.4%).

Conclusions  Following one or more sequential antecedent, documented negative co-tests or HPV tests, women with HPV-positive ASC-US or low-grade squamous intraepithelial lesion might have sufficiently low CIN3+ risk that they do not need colposcopy referral and might instead undergo 6–12-month surveillance for evidence of higher risk before being referred to colposcopy.