Page 261 - 2020_02-Haematologica-web

Obstetric APS and cancer
receiving a diagnosis of unprovoked VTE.13 The data from our cohort are of the same order of magnitude [6/178: 3.4% (1.6%-7.2%)]. Of interest, most of the VTE events observed in our cohort were unprovoked [178/215: 82.8% (77.2%-87.3%)], probably because systematic thromboprophylaxis with low molecular weight heparin was proposed to the women in the Thrombophilia and APS groups, known to be more prone to VTE in the case of an intercurrent risk factor for thrombosis. Another point is that women in the APS group received primary thromboprophylaxis with low-dose aspirin, which may have affected the rate of unprovoked events in that group. We cannot, therefore, consider that the thrombot- ic events observed within our cohort reflect a natural pat- tern of evolution.
There is now clear evidence that chronic low-dose aspirin treatment can prevent one-third of colorectal, gas- tric, and esophageal cancers,14 and possibly some other types of cancer.15 Preclinical and clinical studies show that tumorigenesis and metastasis can be promoted by platelets through a wide variety of crosstalk between platelets and cancer cells.16 It is thus likely that the inci- dence of cancer in our APS group does not correspond to the natural evolution of that group, and that the panel of cancer types developed by the women with APS is not the natural panel. The potentially protective effect of chronic low-dose aspirin treatment does, however, rein- force the finding of a higher incidence of cancers in the follow-up of APS women, and adds support to a wider use of this non-consensual care.
The β2GP1/anti-β2GP1 autoantibody progressively becomes the dominant one in thrombotic APS,17 albeit with some remaining uncertainty in purely obstetric APS. The main finding of this observational study is the asso- ciation between LA and incident cancers; a putative asso- ciation with anti-β2GP1 autoantibody did not reach sta- tistical significance. This could of course be the conse- quence of a lack of statistical power, positive anti-β2GP1 autoantibodies being less prevalent in our women with obstetric APS. It is also possible that the type and strength of aPL antibodies influence the appearance of incident cancer in positive women, in terms of both the types of cancer and in the differential levels of risk. Our study can- not resolve this issue. A more complex model may be needed to explain why some aPL antibodies did not appear to have an effect in this limited first analysis. A further possibility is that another aPL antibody cofactor, not β2GP1, may better explain the increased incidence of cancer in our women with APS. The most likely candi- date for further investigation is coagulation factor II (pro- thrombin), because of the impact of LA.18
The association between aPL antibodies and the increased incidence of cancers is difficult to interpret. There is currently no definitive demonstration of an asso- ciation between chronic hypercoagulability and the risk of cancer, although one prospective study showed that men with higher levels of prothrombin fragments 1+2 had an increased risk of digestive tract cancers during a 10-year follow-up.19 At the phenotypic level, circumstan- tial evidence suggests a role for coagulation factors, par- ticularly tissue factor and thrombin, in the signaling path- ways of tumorigenesis (e.g., angiogenesis, apoptosis, eva- sion, invasion, and metastasis).20-23 Some polymorphisms in the F5, F7, F10, F13A, and PROCR genes, whose effects on the coagulation phenotype are not fully characterized,
are associated with the risk of solid tumors;24 for instance, breast cancer is associated with polymorphisms in the F5, F10 and PROCR genes.25 However, the aPL antibody most significantly associated with incident cancers (i.e., LA)
Table 2A. Incidence of cancer in the three groups of women constituting the NOH- APS cohort. Crude data and unadjusted analysis with the Control group as the reference.
Group
Patient-years of follow-up
Cancer diagnosis:
number of cases.
Annualized rates
of cancer, % (95% CI)
Hazard ratio
95% CI
P
Control
13 260.35
18*
0.14 (0.10-0.21)
1
Thrombophilia
4 662.77
8**
0.17 (0.09-0.34)
1.28
(0.56-2.95)
0.56
APS
8 664.98
26***
0.30 (0.20-0.44)
2.22
(1.22-4.06)
0.0092
*APS: antiphospholipid syndrome; 95% CI: 95% confidence interval; HR: hazard ratio. *Breast cancer (n=10), colon cancer (n=3), endometrial cancer (n=2), pancreatic cancer (n=1), thy- roid cancer (n=1), lung cancer (n=1). **Breast cancer (n=7), colon cancer (n=1). ***Breast cancer (n=12), non-Hodgkin lymphoma (n=3), colon cancer (n=3), pancreatic cancer (n=3), endometrial cancer (n=1), thyroid cancer (n=2),primary brain tumor (n=2).
Table 2B. Associations of clinical parameters and biological parameters in women with an incident cancer during follow-up as compared with women with no cancer.
Univariate analysis HR (95% CI) P
0.0003
Multivariate analysis** aHR (95% CI) P
Clinical associations
Inclusion:
Age, years *
Body mass index, kg/m-2 * Fetaldeath
Secondary pregnancy loss
Follow-up:
Familyhistoryofcancer FamilyhistoryofVTE Family history
of atherothrombosis* Activesmoking Non-cancerous
inflammatory disease Immunosuppressive
treatment Diabetes mellitus* Pregnancyloss Fetal death Stillbirth
Neonatal death Placenta-mediated
complication
Venous thromboembolism Pulmonary embolism Deep vein thrombosis
Arterialthrombosis* 2.89(1.04-8.05) 0.0419
1.15 (1.07-1.24) 1.10 (1.01-1.20)
2.47 (1.28-4.76)
5.13 (1.16-22.7)
0.0002 0.0217
0.0071
0.0311
1.14 (1.06-1.22) 1.10 (1.01-1.19)
0.0284 1.08(0.63-1.86) 0.79 0.70 (0.40-1.21) 0.203
0.72(0.34-1.55) 0.41
0.92(0.22-3.79) 0.91 2.04 (1.07-3.89) 0.0300
1.15(0.49-2.68) 0.75 0.76(0.11-5.52) 0.79
0.74(0.10-5.54) 0.76
5.46 (1.32-22.5) 0.0186 0.87(0.49-1.55) 0.63 0.82 (0.32-2.10) 0.68 0.77 (0.18-3.19) 0.71 1.35 (0.33-5.57) 0.67 1.08 (0.51-2.30) 0.84
1.37 (0.67-2.80) 0.40 1.58 (0.49-5.06) 0.44
1.82(0.86-3.88) 0.119 0.45(0.06-3.30) 0.44 Superficialveinthrombosis*2.13(0.85-5.38) 0.108
Proximal* Distal
Biological associations (comparator: Control group)
APS*
Thrombophilia
2.23(1.22-4.06) 0.0092
1.28(0.56-2.95) 0.56
2.26(1.20-4.24) 0.0115
HR: hazard ratio; 95% CI: 95% confidence interval; aHR: adjusted hazard ratio; VTE: venous thromboembolism; APS: antiphospholipid syndrome. *Variables included in the multivariate analysis.**Likelihoodratioofthemodel:χ2 41.15,10degreesoffreedom,P<0.0001.
haematologica | 2020; 105(2)
495