November 2017

 

Drugging the Cancers Addicted to DNA Repair. JA Nickoloff,  D Jones,  S-H Lee, EA Williamson,  R Hromas. Journal of the National Cancer Institute, 109, Issue 11, 2017, djx059

REVIEW

Defects in DNA repair can result in oncogenic genomic instability. Cancers occurring from DNA repair defects were once thought to be limited to rare inherited mutations (such as BRCA1 or 2). It now appears that a clinically significant fraction of cancers have acquired DNA repair defects. DNA repair pathways operate in related networks, and cancers arising from loss of one DNA repair component typically become addicted to other repair pathways to survive and proliferate. Drug inhibition of the rescue repair pathway prevents the repair-deficient cancer cell from replicating, causing apoptosis (termed synthetic lethality). However, the selective pressure of inhibiting the rescue repair pathway can generate further mutations that confer resistance to the synthetic lethal drugs. Many such drugs currently in clinical use inhibit PARP1, a repair component to which cancers arising from inherited BRCA1 or 2 mutations become addicted. It is now clear that drugs inducing synthetic lethality may also be therapeutic in cancers with acquired DNA repair defects, which would markedly broaden their applicability beyond treatment of cancers with inherited DNA repair defects. Here we review how each DNA repair pathway can be attacked therapeutically and evaluate DNA repair components as potential drug targets to induce synthetic lethality. Clinical use of drugs targeting DNA repair will markedly increase when functional and genetic loss of repair components are consistently identified. In addition, future therapies will exploit artificial synthetic lethality, where complementary DNA repair pathways are targeted simultaneously in cancers without DNA repair defects.

Tumor Microvessel Density as a Potential Predictive Marker for Bevacizumab Benefit: GOG-0218 Biomarker Analyses

C Bais,  B Muelle,r  MF Brady,  RS Mannel, RA Burger,  W Wei,  KM Marien,  MM Kockx, A Husain,  MJ Birrer. Journal of the National Cancer Institute, 109, Issue 11, 2017, djx066

Background  Combining bevacizumab with frontline chemotherapy statistically significantly improved progression-free survival (PFS) but not overall survival (OS) in the phase III GOG-0218 trial. Evaluation of candidate biomarkers was an exploratory objective.

Methods  Patients with stage III (incompletely resected) or IV ovarian cancer were randomly assigned to receive six chemotherapy cycles with placebo or bevacizumab followed by single-agent placebo or bevacizumab. Five candidate tumor biomarkers were assessed by immunohistochemistry. The biomarker-evaluable population was categorized into high or low biomarker-expressing subgroups using median and quartile cutoffs. Associations between biomarker expression and efficacy were analyzed. All statistical tests were two-sided.

Results  The biomarker-evaluable population (n = 980) comprising 78.5% of the intent-to-treat population had representative baseline characteristics and efficacy outcomes. Neither prognostic nor predictive associations were seen for vascular endothelial growth factor (VEGF) receptor–2, neuropilin-1, or MET. Higher microvessel density (MVD; measured by CD31) showed predictive value for PFS (hazard ratio [HR] for bevacizumab vs placebo = 0.40, 95% confidence interval [CI] = 0.29 to 0.54, vs 0.80, 95% CI = 0.59 to 1.07, for high vs low MVD, respectively, Pinteraction = .003) and OS (HR = 0.67, 95% CI = 0.51 to 0.88, vs 1.10, 95% CI = 0.84 to 1.44, Pinteraction = .02). Tumor VEGF-A was not predictive for PFS but showed potential predictive value for OS using a third-quartile cutoff for high VEGF-A expression.

Conclusions  These retrospective tumor biomarker analyses suggest a positive association between density of vascular endothelial cells (the predominant cell type expressing VEGF receptors) and tumor VEGF-A levels and magnitude of bevacizumab effect in ovarian cancer. The potential predictive value of MVD (CD31) and tumor VEGF-A is consistent with a mechanism of action driven by VEGF-A signaling blockade.

Microvascular Density as a Predictive Biomarker for Bevacizumab Survival Benefit in Ovarian Cancer: Back to First Principles? N Ferrara. Journal of the National Cancer Institute, 109, 11, 2017, djx067, https://doi-org.ezproxy.uky.edu/10.1093/jnci/djx067

Vascular endothelial growth factor–A (VEGF-A) is a key regulator of physiological and pathological angiogenesis. Following promising preclinical data showing growth inhibition in multiple tumor xenograft models, a murine anti-VEGF-A monoclonal antibody was humanized to enable clinical trials in cancer patients. This humanized antibody, known as bevacizumab, was first approved by the US Food and Drug Administration (FDA) for previously untreated metastatic colorectal cancer in 2004, after a phase III trial that showed that bevacizumab plus chemotherapy increased both progression-free survival (PFS) and overall survival (OS) relative to chemotherapy alone. These benefits were seen despite the lack of a biomarker to select patients most likely responsive to the treatment. To put this in perspective, a very effective therapeutic like trastuzumab would have required a much larger trial to demonstrate benefits in the absence of selection of breast cancer patients for human epidermal growth factor receptor 2 (HER2) overexpression. Bevacizumab has been tested in numerous tumor types and today is FDA approved in multiple indications, including metastatic cervical cancer, platinum-resistant ovarian cancer (7), and, most recently, platinum-sensitive, recurrent ovarian cancer (http://www.roche.com/media/store/releases/med-cor-2016-12-07.htm). However, not all studies have demonstrated an OS benefit. While this may be attributed, at least in part, to patient crossover from the control group to bevacizumab or other treatment groups, it is clear that the response to bevacizumab and other anti-VEGF agents has been heterogeneous. Although a number of predictive biomarkers for bevacizumab and other VEGF pathway inhibitors have been suggested on the basis of small patient series, including hypertension, tumor imaging, soluble VEGF receptors, circulating proinflammatory cytokines, or gene signatures, none has been prospectively validated yet [reviewed in]. This difficulty might also reflect the complexity of the angiogenesis process, which is influenced by multiple players within the microenvironment, as compared with tumor-intrinsic changes such as oncogene mutations or amplifications. An additional level of complexity—and potentially a confounder—is represented by the use of cytotoxic agents in conjunction with anti-VEGF therapy. In fact, several cytotoxic agents (including paclitaxel) have been shown to have antivascular effects (9), and rebound angiogenesis, mediated by mobilization of myeloid cells, has been reported to be a mechanism of tumor resistance to certain cytotoxics. It has been speculated that most of the benefits of anti-VEGF therapy derive from facilitating tumor delivery of cytotoxic agents through “normalization” of the vasculature (11). However, preclinical studies have clearly shown single-agent activity of VEGF inhibitors in a variety of tumor models (12), including ovarian cancer models. An early study reported that monotherapy with an anti-VEGF antibody resulted in suppression of angiogenesis and growth of human ovarian cancer cells implanted in immunodeficient mice (13). This study also emphasized the importance of long-term VEGF inhibition because interruption of the antibody treatment resulted in resumption of tumor growth as well as ascites formation (13). A more recent study by Mabuchi et al. went further, showing that while combination of bevacizumab with chemotherapy improved survival of mice implanted with ovarian cancer cells relative to chemotherapy alone, the greatest benefit was observed in the group that received long-term “maintenance” with single-agent bevacizumb after the administration of bevacizumab plus chemotherapy (14). The Gynecological Oncology Group (GOG)-218 study, by virtue of its innovative design, is an important study in anti-angiogenesis. Over 1200 patients with newly diagnosed stage III and IV ovarian cancer were randomly assigned to three groups (15). All three groups included paclitaxel and carboplatin for cycles 1 through 6. The control treatment was chemotherapy with placebo added in cycles 2 through 22. Bevacizumab initiation treatment was chemotherapy with bevacizumab (15 mg/kg every three weeks) added in cycles 2 through 6 and placebo added in cycles 7 through 22. Bevacizumab throughout treatment was chemotherapy with bevacizumab added in cycles 2 through 22. Interestingly, bevacizumab throughout was the only treatment group that had a statistically and biologically significant improvement in PFS, the primary end point of the trial. The increase was four or six months, depending on how PFS was evaluated (15). A parallel randomized phase III study, ICON7, also tested a “maintenance” arm, but the dose of bevacizumab was lower (7.5 mg/kg every three weeks) and the improvement in PFS was of lesser magnitude compared with GOG-218, suggesting a dose dependence (16). However, in spite of the improvement in PFS, no statistically significant OS improvement was seen in GOG-218, although crossover from the chemotherapy-alone arm to bevacizumab-containing therapy (or other treatment lines) might have potentially masked an effect on OS. Bais et al. (17) sought to evaluate potential tumor biomarkers from patients in the GOG-218 study. Nine hundred and eighty patients (78.5% of the patients that were enrolled in the trial) were evaluable. Candidate biomarkers were assessed by immunohistochemistry (IHC) after completion of the clinical trial using sections taken from the pretreatment tumor samples. The authors found that while no prognostic or predictive associations were observed for cMet, Neuropilin-1, and VEGFR-2, tumor-VEGF was associated with OS, although not with PFS. Intriguingly, the marker that showed the strongest association with clinical benefit was microvascular density (MVD). The effects of bevacizumab treatment on both PFS and OS were greater in patients with higher MVD in tumor sections. Although the analysis by Bais et al. is retrospective, it was prespecified (17). The study by Bais et al. is important and, if confirmed, is likely to have a major impact in the design of future trials. It represents possibly the largest biomarker study in anti-angiogenesis to show a statistically significant association with benefit, including OS. However, previous studies did not identify MVD as a predictive marker of bevacizumb benefit. For example, Jubb et al. (18) retrospectively evaluated several potential predictive biomarkers, including MVD, from a randomized colorectal cancer study (3) but did not find any correlation with treatment outcomes. However, the samples analyzed accounted for only a fraction of the patients enrolled in the trial (18). Also, in the samples from the GOG-218 trial, MVD was assessed by CD31 IHC (17), while in the study by Jubb et al. it was assessed by CD34 IHC (18), although it is unknown whether this difference may have affected the outcome. It is also possible that the design of GOG-218 may have enabled assessment of markers of bevacizumab outcomes with greater fidelity than other studies because the group that showed benefit received single-agent bevacizumab for the majority of the trial, thus reducing the aforementioned potential confounding effects of chemotherapy. Alternatively, one cannot rule out the possibility that biomarkers predictive of bevacizumab outcomes may be tumor type specific, as suggested for glioblastoma multiforme (19). The actions of VEGF are complex, and recent studies have emphasized, for example, effects on the immune system that could have not been adequately evaluated in studies conducted in immunodeficient mice (20). Nevertheless, it is refreshing that endothelial cells, the main target of VEGF, are back at the center stage. Previous studies showed a correlation between MVD and malignant behavior in human tumors (21), and preclinical studies directly showed a correlation between inhibition of tumor growth by an anti-VEGF antibody treatment and suppression of angiogenesis (22). Intuitively, patients with tumors having the highest MVD and/or VEGF content are expected to derive the greatest benefit from anti-VEGF therapy.

Final efficacy, immunogenicity, and safety analyses of a nine-valent human papillomavirus vaccine in women aged 16–26 years: a randomised, double-blind trial WK Huh, EA Joura, AR Giuliano, O-E Iversen, R Pereira de Andrade, KA Ault, D Bartholomew, RM Cestero, EN Fedrizzi , AL Hirschberg, M-H Mayrand, AM Ruiz-Sternberg, JT Stapleton, DJ Wiley, A Ferenczy, R Kurman, BM Ronnett, MH Stoler, J Cuzick, SM Garland, SK Kjaer, OM Bautista, R Haupt, E Moeller, M Ritter, CC Roberts, C Shields, A Luxembourg.  Lancet, The, 2017-11-11, Volume 390, 10108, 2143-2159.

Background  Primary analyses of a study in young women aged 16–26 years showed efficacy of the nine-valent human papillomavirus (9vHPV; HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58) vaccine against infections and disease related to HPV 31, 33, 45, 52, and 58, and non-inferior HPV 6, 11, 16, and 18 antibody responses when compared with quadrivalent HPV (qHPV; HPV 6, 11, 16, and 18) vaccine. We aimed to report efficacy of the 9vHPV vaccine for up to 6 years following first administration and antibody responses over 5 years.

Methods  We undertook this randomised, double-blind, efficacy, immunogenicity, and safety study of the 9vHPV vaccine study at 105 study sites in 18 countries. Women aged 16–26 years old who were healthy, with no history of abnormal cervical cytology, no previous abnormal cervical biopsy results, and no more than four lifetime sexual partners were randomly assigned (1:1) by central randomisation and block sizes of 2 and 2 to receive three intramuscular injections over 6 months of 9vHPV or qHPV (control) vaccine. All participants, study investigators, and study site personnel, laboratory staff, members of the sponsor’s study team, and members of the adjudication pathology panel were masked to vaccination groups. The primary outcomes were incidence of high-grade cervical disease (cervical intraepithelial neoplasia grade 2 or 3, adenocarcinoma in situ, invasive cervical carcinoma), vulvar disease (vulvar intraepithelial neoplasia grade 2/3, vulvar cancer), and vaginal disease (vaginal intraepithelial neoplasia grade 2/3, vaginal cancer) related to HPV 31, 33, 45, 52, and 58 and non-inferiority (excluding a decrease of 1·5 times) of anti-HPV 6, 11, 16, and 18 geometric mean titres (GMT). Tissue samples were adjudicated for histopathology diagnosis and tested for HPV DNA. Serum antibody responses were assessed by competitive Luminex immunoassay. The primary evaluation of efficacy was a superiority analysis in the per-protocol efficacy population, supportive efficacy was analysed in the modified intention-to-treat population, and the primary evaluation of immunogenicity was a non-inferiority analysis. The trial is registered with ClinicalTrials.gov , number NCT00543543 .

Findings  Between Sept 26, 2007, and Dec 18, 2009, we recruited and randomly assigned 14 215 participants to receive 9vHPV (n=7106) or qHPV (n=7109) vaccine. In the per-protocol population, the incidence of high-grade cervical, vulvar and vaginal disease related to HPV 31, 33, 45, 52, and 58 was 0·5 cases per 10 000 person-years in the 9vHPV and 19·0 cases per 10 000 person-years in the qHPV groups, representing 97·4% efficacy (95% CI 85·0–99·9). HPV 6, 11, 16, and 18 GMTs were non-inferior in the 9vHPV versus qHPV group from month 1 to 3 years after vaccination. No clinically meaningful differences in serious adverse events were noted between the study groups. 11 participants died during the study follow-up period (six in the 9vHPV vaccine group and five in the qHPV vaccine group); none of the deaths were considered vaccine-related.

Interpretation  The 9vHPV vaccine prevents infection, cytological abnormalities, high-grade lesions, and cervical procedures related to HPV 31, 33, 45, 52, and 58. Both the 9vHPV vaccine and qHPV vaccine had a similar immunogenicity profile with respect to HPV 6, 11, 16, and 18. Vaccine efficacy was sustained for up to 6 years. The 9vHPV vaccine could potentially provide broader coverage and prevent 90% of cervical cancer cases worldwide.

Pembrolizumab is effective for drug-resistant gestational trophoblastic neoplasia. E Ghorani, B Kaur, RA Fisher, D Short, U Joneborg, JW Carlson, A Akarca, T Marafioti, SA Quezada, N Sarwar, MJ Seckl. Lancet,  2017-11-25, Vol 390, 10110, 2343-2345.

Gestational trophoblastic disease represents a spectrum of pregnancy related disorders, ranging from pre-malignant hydatidiform mole to malignant tumours, collectively referred to as gestational trophoblastic neoplasia. Gestational trophoblastic neoplasia includes malignant invasive mole, choriocarcinoma, and rare placental site trophoblastic and epithelioid trophoblastic tumours.  1  Globally, approximately 18 000 women are diagnosed with gestational trophoblastic neoplasia annually, most of whom are cured with chemotherapy guided by the sensitive disease response biomarker, human chorionic gonadotropin. However, 0·5–5·0% of women die as a result of multidrug resistance, necessitating novel approaches. Risk factors for poor survival include drug refractory disease,  2  liver or brain metastases,  3 4 and placental site trophoblastic and epithelioid trophoblastic tumours that develop 4 years or more after the antecedent pregnancy.  Anticancer T-cell activity is regulated by multiple suppressive mechanisms, including tumour-expressed programmed cell death ligand 1 (PD-L1) signalling to the T-cell inhibitory receptor (programmed death protein 1 [PD-1]). Monoclonal antibodies that block this pathway, such as the anti-PD-1 drug pembrolizumab, have impressive clinical activity in several cancer types.  Placental expression of paternal antigens make this organ a target for maternal immune recognition during pregnancy, and PD-L1 expression maintains gestational tolerance. In preclinical models, loss of PD-L1 signalling results in fetal rejection.  7  PD-L1 is strongly expressed by gestational trophoblastic neoplasias,  8 9 10  suggesting the ligand is involved in tumour–immune evasion. We therefore hypothesised that targeting PD-1 inhibitory signalling with pembrolizumab might be effective in drug-resistant gestational trophoblastic neoplasia. In this letter, we report the outcomes of four patients treated at Charing Cross Hospital (London, UK) and Karolinska University Hospital (Stockholm, Sweden).  All patients had genetically verified gestational tumours, and patient demographics are summarised in the appendix (pp 1–3) . Patient 1 (aged 39 years) presented in September, 2012, with choriocarcinoma and multiple high risk factors, including liver and brain metastases ( appendix p 3 ). The patient’s primary disease and first relapse in 2013 were treated to remission with multiagent chemotherapy, including high-dose treatment ( figure ). Further chemotherapy for a second relapse in 2015 was ineffective and she progressed through fifth-line treatment. Multiplex immunohistochemistry of a chest wall biopsy sample revealed almost 100% tumour PD-L1 expression and rich peritumoural and focal densities of tumour-infiltrating lymphocytes that were predominantly CD8+ cytotoxic T cells, half of which were PD-1-positive ( figure , appendix p 5 ). Tumour cells were negative for the MHC-I antigen HLA-A and MHC-II, but positive for the immunoinhibitory non-classical MHC-I antigen, HLA-G ( appendix p 5 ). The patient had a serum human chorionic gonadotropin concentration of 80 IU/L, which normalised to less than 5 IU/L after four cycles of pembrolizumab (2 mg/kg, every 3 weeks). Pembrolizumab was discontinued in October, 2015, after five further consolidation cycles. Residual liver lesions regressed on serial imaging and she remains in complete remission more than 24 months later. Patient 2 (aged 44 years) presented in October, 2007, with a mixed placental site trophoblastic and epithelioid trophoblastic tumour. She achieved remission with hysterectomy followed by adjuvant multiagent chemotherapy but relapsed in 2011 and did not respond to further chemotherapy ( appendix p 6 ). Tumour cells in the original hysterectomy sample and a lung metastasis biopsy sample had more than 90% PD-L1 expression, but tumour-infiltrating lymphocytes were absent ( appendix p 6 ). Tumour cells were negative for HLA-A, pan-MHC-II, and HLA-G ( appendix p 6 ; data not shown). After five cycles of pembrolizumab, re-imaging in October, 2015, revealed disease progression consistent with an increasing serum human chorionic gonadotropin concentration, and the patient died 4 months later.  Patient 3 (aged 47 years) presented in April, 2015, with a placental site trophoblastic tumour with metastases to the lung, liver, and brain. Her brain metastases progressed during thirdline therapy ( appendix p 7 ). Considerable treatment-related neuropathy precluded further chemotherapy. Immunohistochemistry of tissue fragments from a uterine biopsy revealed more than 90% PD-L1 expression and the presence of tumour-infiltrating lymphocytes. Tumour cells were negative for HLA-A and pan-MHC-II but positive for HLA-G. After initiation of treatment with pembrolizumab, her serum human chorionic gonadotropin concentration increased from 73 to 4476 IU/L before decreasing after four cycles of treatment. Re-imaging showed a partial response of the pulmonary metastases but multiple new brain lesions ( appendix p 7 ). Her serum and cerebrospinal fluid human chorionic gonadotropin concentrations normalised after eight cycles. After the completion of five consolidation cycles in August, 2016, re-imaging showed residual uterine necrotic tissue only, which was confirmed pathologically. She remained in remission in October, 2017, more than 15 months after completing pembrolizumab treatment.  Patient 4 (aged 37 years) presented in May, 2015, with lung metastatic choriocarcinoma. She achieved remission after five lines of treatment, including high-dose chemotherapy ( appendix p 8 ). Immunohistochemistry of a lung deposit revealed almost 100% tumour PD-L1 expression with dense peritumoural and intratumoural foci of tumour-infiltrating lymphocytes, composed of equal numbers of predominantly PD-1-negative CD8+ cytotoxic and CD4+ helper T cells, with a high number of CD56+ natural killer cells ( appendix p 8 ). Tumour cells were HLA-A and MHC-II negative and HLA-G positive ( appendix p 8 and data not shown). In November, 2015, she relapsed with lung and pelvic nodal disease and a human chorionic gonadotropin concentration of 118 IU/L. Treatment with pembrolizumab was subsequently initiated in December, 2016, with marker normalisation after two cycles ( appendix p 8 ). She completed five consolidation courses of pembrolizumab in June, 2017, and remains in remission more than 5 months later.  Treatment was well tolerated in all four patients with mild (grade 1–2) toxicities managed conservatively ( appendix p 3 ).  Unresectable drug-resistant gestational trophoblastic neoplasia is fatal and anti-PD-1 immunotherapy might be a life-saving treatment. The efficacy and favourable toxicity profile of pembrolizumab make its earlier use an attractive alternative to high-dose chemotherapy. However, the risk of permanent fertility impairment due to lasting anti-trophoblast immunity is a concern that requires further study before pembrolizumab or other immunotherapies can be recommended at an earlier stage in the treatment sequence.  Consistent with previous studies,  8 9  we found gestational trophoblastic neoplasias strongly express PD-L1, which in this small sample was not a biomarker of response to immunotherapy. The phenotypic features, density, and distribution of tumour-infiltrating lymphocytes correlate with anti-PD-1 response,  11  suggesting a causal link between the absence of infiltrating immune cells and outcome in patient 2, who did not respond.  Several cell types might mediate the effect of pembrolizumab on gestational trophoblastic neoplasia rejection. Trophoblasts do not express the classical MHC-I molecules HLA-A and HLA-B, or MHC–II, offering protection from T-cell-mediated placental destruction.  12  We found that gestational trophoblastic neoplasia is similarly negative for HLA-A and MHC-II. The strong presence of infiltrating T cells in responders suggests pembrolizumab might activate HLA-C directed or indirect T cell cytotoxicity. Effectors other than classically restricted T-cells might also be relevant. One candidate is natural killer cells that express PD-1, are cytotoxic towards classical MHC-I- negative cells, and are inhibited by HLA-G, which additionally contributes to the maintenance of gestational tolerance through T-cell suppression.  Upregulated tumour expression of HLA-G by the responders suggests this molecule is important for the inhibition of infiltrating lymphocyte effectors. Beyond T-cell activation, the immune effects of pembrolizumab are not well understood but are potentially of wider relevance, especially as HLA-G expression is a recognised mediator of tumour immune evasion.  Complex restrictions precluded public funding of potentially life-saving off-label treatment with pembrolizumab for patients 1–3, who were treated in the UK. This research letter highlights the need to improve the way novel drugs are funded for rare diseases, for which randomised trials and established licensing pathways are not feasible. On the basis of the evidence presented in this letter, UK public funding of pembrolizumab for drug-resistant gestational trophoblastic neoplasia is now under review.  In conclusion, pembrolizumab represents an important new approach for the management of drug-resistant gestational trophoblastic neoplasia that should strongly be considered in this setting. Tumour-infiltrating lymphocytes and HLA-G expression might identify responders, and our analysis of MHC expression suggests that pembrolizumab has potential effects on cell types other than classically restricted T cells.  We thank the UK Department of Health for their continued funding of the Gestational Trophoblastic Disease Service.  EG received grants from the Wellcome Trust and the National Institute for Health Research (NIHR) Biomedical Research Centre. RAF received grants from Cancer Research UK, the UK Department of Health, Imperial College Experimental Cancer Medicine Centre, and NIHR Biomedical Research Centre. JWC received grants from ThermoFisher, outside the submitted work. MJS received grants from the NIHR Biomedical Research Centre, Cancer Research UK, the UK Department of Health, and Imperial College Experimental Cancer Medicine Centre; reports that the Harris and Trotter Clients Charitable Trust funded pembrolizumab for two of the patients; and received personal fees from Bristol-Myers Squibb, outside the submitted work. All other authors declare no competing interests.

National Estimates of Genetic Testing in Women With a History of Breast or Ovarian Cancer

CP Childers, KK Childers, M Maggard-Gibbons, James Macinko,  Journal of Clinical Oncology 35, no. 34 (December 2017) 3800-3806.  DOI: 10.1200/JCO.2017.73.6314

Purpose In the United States, 3.8 million women have a history of breast (BC) or ovarian cancer (OC). Up to 15% of cases are attributable to heritable mutations, which, if identified, provide critical knowledge for treatment and preventive care. It is unknown how many patients who are at high risk for these mutations have not been tested and how rates vary by risk criteria.

Methods  We used pooled cross-sectional data from three Cancer Control Modules (2005, 2010, 2015) of the National Health Interview Survey, a national in-person household interview survey. Eligible patients were adult females with a history of BC and/or OC meeting select 2017 National Comprehensive Cancer Network eligibility criteria on the basis of age of diagnosis and family history. Outcomes included the proportion of individuals reporting a history of discussing genetic testing with a health professional, being advised to undergo genetic testing, or undergoing genetic testing for BC or OC.

Results  Of 47,218 women, 2.7% had a BC history and 0.4% had an OC history. For BC, 35.6% met one or more select eligibility criteria; of those, 29.0% discussed, 20.2% were advised to undergo, and 15.3% underwent genetic testing. Testing rates for individual eligibility criteria ranged from 6.2% (relative with OC) to 18.2% (diagnosis ≤ 45 years of age). For OC, 15.1% discussed, 13.1% were advised to undergo, and 10.5% underwent testing. Using only four BC eligibility criteria and all patients with OC, an estimated 1.2 to 1.3 million individuals failed to receive testing.

Conclusion  Fewer than one in five individuals with a history of BC or OC meeting select National Cancer Comprehensive Network criteria have undergone genetic testing. Most have never discussed testing with a health care provider. Large national efforts are warranted to address this unmet need.

Testing for BRCA1/2 Mutations.  P Sefton. JAMA. 2017;318(20):2054. doi:10.1001/jama.2017.17280

Changes in genes called BRCA1 and BRCA2 increase a person’s risk of certain types of cancer, especially cancers of the breast and ovaries.  BRCA1 and BRCA2 are types of tumor suppressor genes—genes that produce special proteins needed to repair damaged DNA (genetic material) in cells. Certain mutations (changes) in these genes prevent the repair of damaged DNA. In turn, the presence of unrepaired DNA increases the risk of acquiring other mutations that contribute to the development of cancer.

If you are a woman, harmful mutations in the BRCA1 or BRCA2 genes can greatly increase your risk of developing cancer of the breast or ovaries. Such mutations also can increase your risk of developing cancer of the fallopian tubes, peritoneum (lining of the abdominal cavity), or pancreas. If you are a man, such mutations can increase your risk of developing cancer of the breast, prostate, or pancreas. Some BRCA1/2 gene mutations, if inherited from both parents, are also associated with the development of certain forms of anemia in both women and men.

 

What Factors Influence the Chances of Having a Harmful BRCA1/2 Mutation?

A number of factors can increase your chances of having a harmful BRCA1 or BRCA2 mutation. The figure lists some of these factors. Your doctor or a genetic counselor can provide more information and help you understand these risk factors.

Who Should Be Tested for BRCA1/2 Mutations?

The harmful BRCA1/2 mutations that can lead to serious medical conditions are not common. If you do not already have cancer, you should consider being tested for such mutations if your personal or family medical history reveals factors such as those listed in the figure that make it likely that you might have a harmful BRCA1/2 mutation. Your doctor or a genetic counselor can review your personal and family medical histories and help you decide whether to be tested.

What Do the Test Results Mean?

A positive test result means that you do have a harmful BRCA1/2 mutation and your risk of developing certain cancers, especially of the breast or ovaries, is increased. In addition, a positive result suggests that other family members—such as brothers, sisters, or children—might also have a harmful BRCA1/2 mutation, and they should consider being tested. A positive result does not mean that you (or affected family members) definitely will develop cancer—but knowing that you have a harmful BRCA1/2 mutation can help you and your doctor develop a monitoring plan that helps minimize risks for you and your family members.

A negative test result means that you most likely do not have a harmful BRCA1/2 mutation—but the implications of that information depend on factors such as your personal and family medical histories. For example, if your personal or family histories suggest that you might be at risk of having a harmful BRCA1/2 mutation but no close relatives have been identified as having such a mutation, you might still have a BRCA1/2 mutation that was not identified by the test and that has not yet been identified as harmful. Your negative test result is considered true negative only if you also have a close relative identified as having a harmful BRCA1/2 mutation. However, a true-negative result does not mean that you definitely will not develop cancer. You still have an average overall risk of developing a cancer unrelated to BRCA1/2 mutations.  An uncertain (ambiguous) test result means that you do have a BRCA1/2 mutation, but the particular mutation has not been identified as contributing to cancer risk.

The interpretation of results of mutation testing is complex. Your doctor or a genetic counselor can help interpret results and also recommend specific action you should take, especially if you have received a positive test result.

Precision Oncology: Between Vaguely Right and Precisely Wrong.  A Brock and S Huang, Cancer Res; 77(23); 6473–9. DOI: 10.1158/0008-5472.CAN-17-0448 Published December 2017.

Precision Oncology seeks to identify and target the mutation that drives a tumor. Despite its straightforward rationale, concerns about its effectiveness are mounting. What is the biological explanation for the “imprecision?” First, Precision Oncology relies on indiscriminate sequencing of genomes in biopsies that barely represent the heterogeneous mix of tumor cells. Second, findings that defy the orthodoxy of oncogenic “driver mutations” are now accumulating: the ubiquitous presence of oncogenic mutations in silent premalignancies or the dynamic switching without mutations between various cell phenotypes that promote progression. Most troublesome is the observation that cancer cells that survive treatment still will have suffered cytotoxic stress and thereby enter a stem cell–like state, the seeds for recurrence. The benefit of “precision targeting” of mutations is inherently limited by this counterproductive effect. These findings confirm that there is no precise linear causal relationship between tumor genotype and phenotype, a reminder of logician Carveth Read’s caution that being vaguely right may be preferable to being precisely wrong. An open-minded embrace of the latest inconvenient findings indicating nongenetic and “imprecise” phenotype dynamics of tumors as summarized in this review will be paramount if Precision Oncology is ultimately to lead to clinical benefits.

Clonality, Heterogeneity, and Evolution of Synchronous Bilateral Ovarian CancerX Yin, Y Jing, M-C Cai, P Ma, Y Zhang, C Xu, M Zhang, W Di and G Zhuang.  Cancer Res; 77(23); 6551–61.  DOI: 10.1158/0008-5472.CAN-17-1461

Synchronous bilateral ovarian cancer (SBOC) represents a relatively frequent occurrence and clinically relevant diagnostic dilemma. Delineation of its clonal architecture, genetic heterogeneity, and evolutionary trajectories may have important implications for prognosis and management of patients with SBOC. Here, we describe the results of next-generation whole-exome or whole-genome sequencing of specimens from 12 SBOC cases and report that bilateral tumors from each individual display a comparable number of genomic abnormalities and similar mutational signatures of single-nucleotide variations. Clonality indices based on tumor-specific alterations supported monoclonal origins of SBOC. Each of the ovarian lesions was nevertheless oligoclonal, with inferred metastatic tumors harboring more subclones than their primary counterparts. The phylogenetic structure of SBOC indicated that most cancer cell dissemination occurred early, when the primary carcinoma was still relatively small (<100 million cells). Accordingly, the mutation spectra and mutational signatures of somatic variants exhibited pronounced spatiotemporal differences in each patient. Overall, these findings suggest that SBOCs are clonally related and form through pelvic spread rather than independent multifocal oncogenesis. Metastatic dissemination is often an early event, with dynamic mutational processes leading to divergent evolution and intratumor and intertumor heterogeneity, ultimately contributing substantially to phenotypic plasticity and diverse clinical course in SBOC.

IL10 Release upon PD-1 Blockade Sustains Immunosuppression in Ovarian CancerP Lamichhane, L Karyampudi, B Shreeder, J Krempski, D Bahr, J Daum, KR Kalli, EL Goode, MS. Block, MJ Cannon, KL Knutson.  Cancer Res; 77(23); 6667–78 DOI: 10.1158/0008-5472.CAN-17-0740

Ligation of programmed cell death-1 (PD-1) in the tumor microenvironment is known to inhibit effective adaptive antitumor immunity. Blockade of PD-1 in humans has resulted in impressive, durable regression responses in select tumor types. However, durable responses have been elusive in ovarian cancer patients. PD-1 was recently shown to be expressed on and thereby impair the functions of tumor-infiltrating murine and human myeloid dendritic cells (TIDC) in ovarian cancer. In the present work, we characterize the regulation of PD-1 expression and the effects of PD-1 blockade on TIDC. Treatment of TIDC and bone marrow–derived dendritic cells (DC) with IL10 led to increased PD-1 expression. Both groups of DCs also responded to PD-1 blockade by increasing production of IL10. Similarly, treatment of ovarian tumor–bearing mice with PD-1 blocking antibody resulted in an increase in IL10 levels in both serum and ascites. While PD-1 blockade or IL10 neutralization as monotherapies were inefficient, combination of these two led to improved survival and delayed tumor growth; this was accompanied by augmented antitumor T- and B-cell responses and decreased infiltration of immunosuppressive MDSC. Taken together, our findings implicate compensatory release of IL10 as one of the adaptive resistance mechanisms that undermine the efficacy of anti–PD-1 (or anti–PD-L1) monotherapies and prompt further studies aimed at identifying such resistance mechanisms.

The immunopeptidomic landscape of ovarian carcinomas.  H Schuster, JK Peper, H-C Bösmüller, K Röhle, L Backert, T Bilich, B Ney, MW Löffler, DJ Kowalewski, N Trautwein, A Rabsteyn, T Engler, S Braun, SP Haen, JS Walz, B Schmid-Horch, SY Bruckerg, D Wallwiener, O Kohlbacher, F Fend, H-G Rammensee, S Stevanović, A Staebler,  P Wagner.  PNAS 114 (46), 2017. E9942–E9951, doi: 10.1073/pnas.1707658114.

Abstract  Immunotherapies, particularly checkpoint inhibitors, have set off a revolution in cancer therapy by releasing the power of the immune system. However, only little is known about the antigens that are essentially presented on cancer cells, capable of exposing them to immune cells. Large-scale HLA ligandome analysis has enabled us to exhaustively characterize the immunopeptidomic landscape of epithelial ovarian cancers (EOCs). Additional comparative profiling with the immunopeptidome of a variety of benign sources has unveiled a multitude of ovarian cancer antigens (MUC16, MSLN, LGALS1, IDO1, KLK10) to be presented by HLA class I and class II molecules exclusively on ovarian cancer cells. Most strikingly, ligands derived from mucin 16 and mesothelin, a molecular axis of prognostic importance in EOC, are prominent in a majority of patients. Differential gene-expression analysis has allowed us to confirm the relevance of these targets for EOC and further provided important insights into the relationship between gene transcript levels and HLA ligand presentation.

Significance 

Despite the revolution in cancer therapy initiated by checkpoint inhibitors, durable clinical responses remain sporadic in many types of cancer, including ovarian cancer. Understanding which antigens are essentially presented by tumor cells and further able to be recognized by T cells provides a major step toward novel effective targeted immunotherapies. In this study, we comprehensively analyzed the immunopeptidomic landscape of ovarian carcinoma and compared it to variety of benign sources to identify antigens exclusively presented on tumor cells. With personalized therapies moving into the focus of clinical cancer therapy, we further present insights on how gene-expression analysis and immunohistochemistry can support antigen selection for individualized immunotherapy.