This study provides important and unpublished information on the impact of NSPD on reducing levels of local and systemic inflammatory markers in women with periodontitis and breast cancer when performed before chemotherapy. This finding raises two important perspectives suggesting periodontal treatment is preferred before chemotherapy. First, the elimination of infection/inflammation foci would substantially reduce the risk of acute lesions for the patient, such as mucositis, and, consequently, bacteremia (sepsis) during the antineoplastic treatment process [14,15]. Second, and directly related to our results, would be the fact that a systemic decrease in the inflammatory mediators' levels could be understood as an important adjuvant for antitumor therapy since it has been discussed that interference in cytokine-mediated signaling pathways can bring benefits and prevent possible metastasis[12,13,20,21]. In GCF samples, TGF-β and IL-17 concentrations were statistically reduced (p<0.05) one week after SRP. Decreased TGF-β levels after NSPT (p<0.05) in GCF was found by Pamuk et al. . These results were similar to our study. Escobar et al.  observed a reduction in TGF-β levels in GCF after seven days of SRP. Regarding IL-17, Mistry et al.  also found significant decreases of this cytokine in GCF after three months of SRP, associated or not with antimicrobial photodynamic therapy. Thus, validating the role of NSPT in the control of local inflammation, regardless of the treatment modality.
Also, TGF-β levels were reduced in serum before and after NSPT (p<0.05). Khalaf et al.  showed that TGF-β levels are higher in serum, GCF and saliva of patients affected by periodontitis when compared to healthy controls, and this marker may influence systemic inflammatory disorders. High concentrations of this cytokine have been associated with a worse prognosis of breast cancer because it is involved in processes that stimulate tumor promotion and metastases, such as angiogenesis and immune system evasion [26,27]. Recently, researchers have defended the idea that blockages of TGF-β signaling pathways, through biological or pharmacological inhibitors, may be promising immunotherapy for breast cancer treatment [28,29].
Although no statistically significant (p>0.05), decreased levels of cytokines IL-1β and TNF-α in GCF were observed. Previous data found a significant decrease in these markers in GCF after NSPT, in normosystemic patients [30,31]. Although the difference was not significant, a trend towards a reduction in these markers was observed. Similarly, serum concentrations of IL-1β, TNF-α and IL-17 showed a slight tendency to decrease (p>0.05). Previous studies that assessed clinical periodontal parameters and biomarkers in serum, before and after NSPT evidenced improvement in clinical parameters and diminished IL-1β, TNF-α and IL-17 levels in normosystemic patients with periodontitis [32,33].
Particular attention should be given to these three inflammatory markers (IL-1β, TNF-α and IL-17), since they have been associated with processes that lead to tumor expansion and metastasis and, consequently, to a worse prognosis of malignant neoplasm of the breast.[11,34,35]. Therefore, recently, the scientific community has proposed adjuvant therapeutic strategies that aim to block intracellular signaling pathways mediated by these cytokines and thus prevent metastasis and improve the prognosis of cancer [12,13,20,21].
Likewise, the present study quantified the four inflammatory markers in three different environments, and identified them at baseline and one week after NSPT in GCF and serum. Due to ethical issues, TM samples could only be obtained at the time of biopsy. These cytokines have been commonly related to immunopathogenesis of periodontitis and breast cancer and our data corroborate the idea that inflammation associated with cancer is similar to that observed in chronic inflammation, especially concerning Th1, Th2 and Th17 responses [5,10,12]. For Freudenheim et al. , the presence of periodontopathogenic bacteria in the region of the breast tumor and mediators of chronic inflammation plays an active role in carcinogenesis and could explain an association between both diseases. Güven et al.  and Jia et al.  highlighted that immunoinflammatory mechanisms may be responsible for increasing the chances of cancer development in those individuals who have periodontal disease.
Both diseases are prevalent diseases in adults over the age of 35 . In the present study, the mean age for women was 52.4 years. We chose to maintain the same age pattern in the selection of patients to avoid interference of this factor in the results. Another relevant aspect was the lower number of teeth in the population studied, accounting for an average of 22 dental units. Many studies have assessed the association of periodontal diseases and cancer and performed a correlation between tooth loss with increased risk of malignant neoplasms [39, 40]. Amódio et al.  and Vargas-Villafuerte et al.  also found fewer dental units remaining in a population with the same characteristics as the subjects evaluated in our study.
In this study, periodontal parameters characterized a similar pattern of periodontitis, represented by higher values of PI, PD, CAL, and BOP, when compared to periodontically healthy individuals . Therefore, patients were diagnosed with generalized periodontitis stage III grade B . it is worth mentioning that, although periodontitis is associated with many systemic conditions , women with other diseases, besides invasive ductal carcinoma, were not included to avoid interference in the results.
The data related to the diagnosis of breast cancer showed that the patients had a similar pattern of neoplasia, as 100% presented a diagnosis of invasive ductal carcinoma and absence of metastasis at the time of collection. Most women had a more favorable course of the disease (Table 2). The histological grades are based on differentiation from normal breast cells. Grade 1 represents cells with normal appearance and slow growth, grade 2 with mixed characteristics and grade 3 with abnormal cells of rapid and aggressive growth. These cells may or may not have receptors for estrogen and progesterone, hormones that stimulate their growth. The presence of receptors is related to slow tumor growth and better response to hormone therapy compared with the absence of receptors. In addition, breast cancers may have a protein excess that promotes their growth, which corresponds to HER2. Women with HER2-positive breast cancer have faster and more aggressive tumor growth .
In this research, women diagnosed with cancer for the first time and not undergoing previous treatment (chemotherapy, radiotherapy or mastectomy) were chosen to avoid the interference of these therapies in periodontal and systemic conditions, reducing the number of biases and impaired results. Antineoplastic treatment side effects may alter oral cavity and systemic conditions of individuals. For example, the direct stomatotoxicity of chemotherapy drugs can affect the gingiva by inducing marginal gingivitis and periodontitis or aggravating pre-existing periodontal conditions, besides the risk of systemic complications resulting from immunosuppression [42,45].
On the other hand, the small sample size may have contributed to the results found and constituted a limitation of this study. Many women did not agree to participate due to the psychological issues associated with breast cancer. It is suggested that future long-term studies follow the effects of NSPT in women with breast cancer and correlate the findings with the prognosis and response to antineoplastic treatment.
Thus, NSPT can be an important tool in the multidisciplinary approach of women with breast cancer and periodontitis before chemotherapy, as it decreased TGF-β levels in serum and GCF and IL-17 concentrations in GCF of these patients.