Autoimmune diseases and hypersensitivities improve the prognosis in ER-negative breast cancer

Immunomodulatory antibodies have been used in phase III trials on metastatic melanoma to enhance anti-tumor immunity. One target protein studied in clinical trials for cancer treatment is Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4). CTLA-4 is expressed on the surface of upregulated T-cells and has an inhibitory effect on T-cell activation. CTLA-4 plays an important role in the induction of tolerance to self-antigens (Sanderson et al. 2005; Attia et al. 2005). A blockade of CTLA-4 enhances anti-tumor immune actions and improves survival in metastatic malignant melanoma (Sanderson et al. 2005; Attia et al. 2005; Hodi et al. 2010; Simeone & Ascierto 2012). However, administration of this anti-CTLA-4 antibody is a double-edged sword. There is a strong correlation between the induction of tumor regression and grade 3/4 autoimmune toxicity. Another well-studied target protein of this kind is Programmed Death-1 (PD-1). PD-1 is expressed on activated T-cell and has an inhibitory effect on the effector phase of the T-cell response. A blockade of PD-1 has been shown to improve survival in various forms of stage 4 cancers. Adverse effects are mainly immune system related, but not as severe as those observed when using an anti-CTLA-4 antibody (Brahmer et al. 2012; Topalian et al. 2012).

Autoimmunity is the failure of an organism to recognize its own parts as self (Marrack et al. 2001; Atassi & Casali 2008). An epidemiological study in Denmark showed that the prevalence of 31 different AD in the population exceeded 5%. Diseases classified as AD in that study by Eaton et al. can be seen in Additional file 1: Table S1 (Eaton et al. 2007). Other conditions with a dysregulated immune system include asthma and allergies, which are both examples of HS. In both allergies and asthma, T-cell immune and inflammatory pathways are the main participants (Ahmad Al Obaidi et al. 2008; Cookson 2004; Kumar & Abbas 2007).

The hyperreactivity of the immune system in AD, allergies and asthma could possibly be beneficial for patients with cancer because of an increased tendency to attack the tumor cells. The mutated cancer cells have an altered protein expression and behavior, which enables the immune system to recognize them as malignant (Weinberg 2007). Hence, our hypothesis was that patients with AD or other HS such as asthma and allergies have a better overall survival rate compared to patients without AD or HS conditions. We decided to investigate this using BC as a model.

Cancer incidence among people with AD or HS has been studied previously, with conflicting results (Vojtechova & Martin 2009; Van Hemelrijck et al. 2010; Hwang et al. 2012; Hemminki et al. 2012; Turesson & Matteson 2012; Landgren et al. 2011). Cancer prognosis among the same patients has not been researched to the same extent and they focus mainly in specific diseases (Ji et al. 2011). The aim of this study was to investigate if BC patients with coexisting AD or HS have a better overall cancer survival compared to BC patients without these comorbidities.

The study material was a cohort consisting of 1705 patients diagnosed with BC. Part of the patient material has been used in previous studies (Ellberg et al. 2012; Ellberg et al. 2010; Ellberg & Olsson 2011; Jernstrom et al. 1999). All patients were seen by the same physician at the Department of Oncology, Skåne University Hospital, Lund. The area of uptake is population-based and has been estimated to cover 300,000 patients in the southern parts of Sweden (overall population 1.5 million). The period of recruitment spans from Jan 1^st 1980 to Dec 31^st 2010. All subjects were interviewed through a standardized questionnaire filled out by the physician. This questionnaire contained information about date of birth, comorbidities, BC screening habits, parity, age of menarche, age of menopause, body mass index (BMI), ever-use of hormonal replacement therapy (HRT) and ever-use of oral contraceptive pills (OCP). Tumor stage, ER-status of the tumor and the date of diagnosis were gathered from pathological reports and patients’ charts. Follow-up was performed until Jan 1^st 2011 using the Swedish Civil Register as source. Informed consent was collected from all patients and the study was approved by an ethical board in Sweden (No 110–92).

The cohort was split in to three groups based on AD, HS and non-AD/HS. The criteria of inclusion for each group were report of having AD of any kind (y/n) (Additional file 1: Table S1), report of having type 1 HS, eczema or urticaria (y/n) and no report of having AD or HS, respectively. A fourth group (AD-HS) was constructed as well including both AD and HS. Throughout the entire study, the control group to an analyzed patient group was the corresponding counterpart of the cohort.

Any thyroid diseases of unspecified etiology found among recorded comorbidities were handled as follows. Patients with a reported diagnosis of hypothyroidism, hyperthyroidism, thyrotoxicosis or thyroiditis were included into AD. Patients with a reported diagnosis of goiters, levothyroxine use and thyroid surgery were excluded. Diabetes type I was included as an AD in the study. Diagnosed diabetes with the slightest uncertainty of type was classified as type II and hence excluded from the AD group.

ER-status was missing in 580 cases due to the fact that it was not performed in the clinic at the time of diagnosis with the exception of advanced BC. 341 cases were missing information about screening and out of these 315 were premenopausal. An assumption was made that none of these patients underwent screening, mainly due to young age.

We chose to study overall survival with age stratification. Other types of survival as breast cancer specific survival or relative survival were not studied. Two age cut-offs were used; the first at age 65 years old at time of BC diagnosis to reduce the influence on mortality due to comorbidities. The second cut-off was set at 50 years old at time of BC diagnosis to distinguish between pre- and postmenopausal. The median age of menopause in this material was 50 years.

Our aim was to investigate if AD or HS constitute protective factors for overall survival among BC patients. This study showed a statistically significant overall survival benefit for patients diagnosed with an ER-negative BC if they had a concurrent diagnosis of an AD or a HS. Premenopausal BC patients with AD or HS had an overall survival advantage compared to those without these comorbidities.

This raises the question of the mechanism behind the better overall survival for patients with co-existing AD or HS. As mentioned in the introduction, successful immunostimulatory therapy is often associated with the development of an AD. Since the mutated cancer cells have developed host immune evasion strategies, an overactive immune system that reacts to self-antigens may discover and target cancer cells more readily. From our study, these benefits were more evident in young patients and in those ER-negative BC, but were less clear for other patients.

In most analyses, the difference between the groups was weakened when adjusted for tumor size, lymph node involvement and distant metastases. A possible explanation for this might be that patients with AD or HS had less advanced tumors at time of diagnosis and/or an effect of exclusion of patients with missing information. It might also be that coexistence of AD or HS retards or inhibits tumor progression. Another possible reason is that patients with AD or HS have closer and more regular contact with medical health care and therefore the tumors are found at an earlier stage. Lower mortality observed among patients with AD or HS may also represent the effect of a generalized increase in health awareness.

ER-negative BC patients with AD or HS still exhibited significant overall survival differences even after adjusting for tumor size and lymph node involvement. Furthermore, adjustment for BC screening was made, since BC found through screening has a better prognosis due to earlier detection (Nystrom et al. 2002). Among patients with ER-negative tumors, screening detection did not weaken the result. This indicates that TN-stage and screening detection probably do not influence the longer overall survival for patients with ER-negative tumors and coexisting HS or AD.

Why AD and HS is associated with a better overall survival specifically among the ER-negative BC patients is not known. Compared to ER-positive tumors, the ER-negative are associated with a poorer prognosis, fewer treatment strategies and in generally, a worse tumor grade and hence a more aggressive biological behavior (Putti et al. 2005). Considering the results from our study, there seems to be a protective effect from AD or HS which possibly contributes to decrease the tumor progression. In a recent study by Calabro et al., it is indicated that lymphocyte infiltrate (LI) is associated with survival, but it has opposite effects in ER-positive compared to ER-negative BC patients. A high LI of ER-positive BC patients was associated with a worse prognosis. However, a high LI in ER-negative BC patients was associated with a better overall survival for these patients. LI occurs as a reaction of the organism to the growing tumor mass. Further, Calabro et al., suggest, that the results might reflect intrinsic differences in the biology of the breast-tumor subtypes and also a difference in tumor immune surveillance. ER-status seems to be important for this differentiation (Calabro et al. 2009). This finding points in a similar direction as our result for the ER-negative BC patients, in which they both suggest a specific molecular mechanism through which the immune system effectively inhibits growth of ER-negative tumors. Our suggestion is that LI is higher in AD or HS patients, compared with patients without these conditions. Given that our theory is true, another conceivable explanation for our result could therefore be that an ER-negative BC with a high LI, perhaps caused by an AD or HS, after given therapy more efficiently attacks the tumor cells, than an ER-negative tumor with a low LI. For the ER-negative tumors, where no satisfactory treatment is available, the LI serves as an important supplement defense line for the body.

Patients with ER-negative BC had a statistically significant better overall survival when they had a history of AD or a HS. The overall survival was better among premenopausal patients with AD or HS compared to patients without AD or HS. These findings need to be validated in an independent material. If an over-activated immune system that accompanies a coexisting AD or HS gives a longer survival for BC patients, an immune activation is a possible future target for treatment, especially for patients with ER negative tumors and for young patients.