Research Article - Biomedical Research (2016) Volume 27, Issue 4
Age differences of morbidity of a right and left sided breast cancer: influence of chronic pathology of internal genitals and reproductive organs surgeryDmitrenko Alexey Petrovich*
State Budgetary Institution of the Rostov region “Oncologic dispensary”, Russian Federation, Russia
- *Corresponding Author:
- Dmitrenko Alexey Petrovich
State Budgetary Institution of the Rostov region “Oncologic dispensary”
Accepted date: March 25, 2016
Breast cancer, Breast cancer morbidity, Antitumoral resistance, Tumor laterality, Reproductive organs surgery.
Influence of chronic pathology of internal genitals and reproductive organs surgery (ROS) on a breast cancer (BC) morbidity is actively studied. However results are ambiguous. Especially it concerns ROS [1-4]. Most of researchers consider that with some slip of the tongue of ROS reduces a BC risk [5-10]. But there is no full understanding of fundamental mechanisms of this phenomenon yet. In the context of the vast majority epidemiological and case-control of researches the role of internal genitals in an BC etiology is reduced only to a hormonal factor. However on this aspect there are contradictions too. So, Davelaar et al. using at patients with ROS an estradiol as replacement therapy did not find increase in risk of BC .
Nevertheless, influence of ROS is not limited only to change of the hormonal status. By numerous experiments it is shown that ROS leads to functional and morphological changes of a peripheral and central nervous system [12-16]. Thus, considering only a hormonal factor as the main effect of ROS, we unreasonably exclude other important mechanisms of antitumoral resistance.
The tumor laterality remains inexplicable aspect of a BC epidemiology [17-24]. By results of numerous researches it was shown that BC mainly unilateral process (frequency of the bilateral BC only 1-5%). As the BC in many respects has the genetic nature and distinctly depends on a hormonal factor, naturally there is a question: why the tumor arises only in one mammary gland if both mammary glands have equal risk? It is possible to answer this question, having only defined how symmetry of risks is broken and what can promote it.
By experiments it was determined that ROS can influence on mechanisms of functional asymmetry of a brain. These reactions have lateral specificity and depend on age of experimental animals [25-31]. By other remarkable works of neurophysiologists has been determined the dependence of BC from brain functional asymmetry [32-34].
The theory about possible influence of the status of internal genitals on BC laterality lack clinical confirmation. I.e. in literature we did not find clinical researches with such design. We try to progress in studying of this question. The purpose of this research is an assessment of age differences of morbidity of a right-sided and left-sided BC (i) at the considerable chronic pathology of internal genitals demanding surgical treatment and (ii) after ROS.
Materials and Methods
The retrospective analysis of sampling of patients with BC (n=2060) is carried out. From them 120 (5.8%; CL 95%: 3.8-7.7%) patients with BC which manifested before of ROS, and 83 (4.02%; CL 95%: 2.0-5.9%) patients with BC which manifested after ROS. ROS had not 1857 patients (90.1%; CL 95%: 86.7-93.4%). The age structure of morbidity of BC which manifested before ROS (BC-ROS group; n=120) and after ROS (ROS-BC group; n=83) were compared. Patients without ROS formed the control group (n=1857). The BC laterality and age at the moment of BC verification were considered.
The statistical analysis is carried out with use of the programs “Statistica 8.0”, “SPSS Statistics 23”, “Excel”. Comparison of ranks of data was carried out by the Kruskal-Wallis test. Value p<0.05 was considered as the statistically significant.
In group BC-ROS the most often there was a hysterectomy with ovaries - 96 (80.0%) cases, a bilateral ovariectomy was more rare - 24 (20.0%) cases. We have studied reasons of ROS. The bilateral ovariectomy (n=24) and hysterectomy with ovaries (n=24) were carried out with the purpose of surgical castration (n=52; 43.3%); at 41 of them at postoperative histologic research benign diseases of a uterus and ovaries are revealed (polycystic ovary syndrome, uterine fibroids, etc.). In 14 (11.6%) cases the reasons of ROS were malignant tumours of a uterus (n=8) and ovaries (n=6). In other cases the reasons of ROS were benign diseases of a uterus and ovaries (uterine fibroids, endometriosis, polycystic ovary syndrome, etc.) - 54 (45.0%) cases.
In group ROS-BC most often there was a hysterectomy with ovaries - 45 (54.2%) cases. A hysterectomy without ovaries was more rare - 16 (19.3%) cases. The hysterectomy with unilateral ovariectomy - 14 (16.8%) cases. The only unilateral ovariectomy - 8 (9.6%) cases. Thus, hysterectomy was done to 90.3% of the patients of this group, bilateral or a unilateral ovariectomy - 80.6% of patients. The reasons of ROS were mainly benign diseases of a uterus and ovaries - uterine fibroids, polycystic ovary syndrome, adenomatous hyperplasia of endometrium, dermoid cysts of ovaries, etc. In 9 cases the reasons of ROS were malignant tumours of a uterus (n=5) and ovaries (n=4).
Due to the retrospective character of the research we had no possibility to receive the full information on a state of internal reproductive organs of the patients of control group. Quite possibly, these patients also had pathology of a uterus and ovaries. But as it did not demand surgical treatment, it is empirically possible to assume that this pathology was considerably less expressed, than at patients of BC-ROS and ROS-BC groups.
In the group BC-ROS the left-sided BC was manifested significantly at younger age, than the right-sided BC (р=0.009). The morbidity median (Me [25%; 75%]) of the leftsided BC (n=53) was 42.0 [38.0; 47.0] years, the right-sided BC (n=67) - 46.0 [41.7; 52.0] years. In control group the age structure of left-sided and right-sided BC did not differ (р=0.86); the median of age both in that and in other case was 57.0 [47.0; 66.0] years (Figure 1).
In the group ROS-BC the patients had ROS aged from 33 till 68 years; the median was 45.0 [41.5; 52.5] years. At patients with right-sided BC the ROS was carried out significantly earlier, than at patients with the left-sided BC (р=0.003). So, patients with the right-sided BC had ROS at 43.0 [39.0; 49.0] years, patients with the left-sided BC - at 48.5 [43.3; 56.0] years. The assessment of statistical dependence of such variables as age during ROS and BC laterality has shown, what the earlier ROS was carried out, the higher was a probability of right-sided BC, the later - the higher was the probability of leftsided BC (р=0.017). The time interval between the ROS and manifestation of the BC at patients with a right-sided and leftsided cancer did not differ (р=0.56), the median was there and there 108.0 [48.0; 175.5] months.
In this group the manifestation of left-sided BC (n=40) happened much later, than among patients of control group (р=0.015). It is also necessary to note, that after 65 years the difference of age structure disappeared (Figure 2). At rightsided BC the age structure of the patients of the group ROSBC (n=43) and control group formally did not differ (р=0.39). However, the attitude of cumulative curves to each other forms "scissors" crossing in the point corresponding to 50 years that allows to single out two periods with a boundary in 50 years. I.e. in the age period before 50 years among the patients of the group ROS-BC the manifestation of the BC occurred significantly later, than among the patients of the control group (р=0.007). However in the age periods after 50 years the manifestation of the BC occurred significantly earlier, than among patients of control group (р=0.03). As a result we see, that at the group ROS-BC the patients with right-sided BC were significantly younger than the patients with left-sided BC (р=0.025). The median of a morbidity of right-sided cancer was 53.0 [47.7; 61.0] years, left-sided cancer - 61.0 [53.0; 65.0] years.
Thus, it is possible to formulate the main conclusions of research:
At the considerable chronic pathology of internal genitals the BC diagnosing in the left breast happens at younger age, than in the right breast.
After ROS because of the considerable chronic pathology of internal genitals the BC diagnosing in the left breast happens at later age, than in the right breast.
The considerable chronic pathology of internal genitals and its surgical treatment is a factor of age differences of morbidity of right and left-sided BC.
The results of analysis of the group BC-ROS allow to assume, that the left breast directly or is indirectly more sensitive to negative influence of a considerable chronic pathology of internal genitals, than right breast. Perhaps, there is a physiological state at which the combination of systemic and local factors defines unilateral decrease of antitumoral resistance of mammary glands and internal genitals are involved in it. Anyhow, as a result we observe that among the women having a considerable pathology of internal genitals, the deficiency of antitumoral resistance in the left breast is formed earlier, than in the right breast.
According to the results of comparative analysis in the group ROS-BC it is possible to assume, what the ROS changes antitumoral resistance of an organism too. Apparently, the influence of ROS on the existing right-sided and left-sided deficiency of antitumoral resistance has a different orientation: increase of antitumoral resistance at presence of left-sided deficiency and additional decrease of antitumoral resistance at presence of right-sided deficiency. Actually, the patients with the right-sided BC was significantly younger, than the patients with the left-sided BC. I.e. after ROS the left-sided cancer is diagnosed significantly later in comparison with the control group and right-sided cancer. Perhaps, ROS softens the leftsided deficiency of antitumoral resistance. This effect of ROS was observed only till 65 years. In the subsequent (in an involution phase), perhaps, the role of internal genitals in formation of lateral deficiency of antitumoral resistance is little significant.
In 1993 model of disturbance of symmetry of antitumoral resistance was offered . According to this model, unilateral oncological process in breasts is the sign of disparity of antitumoral resistance of didymous elements of a functional system. As reason of genesis and growth of tumoral illness, the model envisage the presence of unilateral structurally functional deficiency of nervous control as a result of pathological functioning of a hypothalamic-ovarian axis. The model is based on an assumption, that the factors of unilateral decrease of antitumoral resistance have the immediate attitude to features of female generative processes and brain asymmetries. In fact, this model of disturbance of symmetry of antitumoral resistance is a continuation of fundamental works by Balitsky and Volegov dedicated to studying of antitumoral resistance of an organism [36,37]. Researches of these scientists convincingly showed modulating influence of the nervous system on mechanisms of antitumoral resistance.
The author thanks Doctor Poroshenko AB for the help in interpretation of results of research.
Conflicts of Interest
The author declares that he has no conflict of interests.
- Moore DH, Moore CT. Breast carcinoma etiological factors. Adv Cancer Res 1983; 40: 189-253.
- Schairer C, Persson I, Falkeborn M, Naessen T, Troisi R, Brinton LA. Breast cancer risk associated with gynecologic surgery indications for such surgery. Int J Cancer 1997; 17; 70: 150-154.
- Woolcott CG, Maskarinec G, Pike MC, Henderson BE, Wilkens LR, Kolonel LN. Breast cancer risk and hysterectomy status: the Multiethnic Cohort study, Cancer Causes Control 2009; 20: 539-547.
- Press DJ, Bernstein L. Invited Commentary: Reproductive Organ Surgeries and Breast Cancer Risk—Apples, Oranges, or Fruit Cocktail? American Journal of Epidemiology 2013; 177: 500-503.
- Press DJ, Sullivan-Halley J, Ursin G, Deapen D, McDonald JA, Strom BL, Norman SA, Simon MS, Marchbanks PA, Folger SG, Liff JM, Burkman RT, Malone KE, Weiss LK, Spirtas R , Bernstein L. Breast Cancer Risk and Ovariectomy, Hysterectomy, and Tubal Sterilization in the Women's Contraceptive and Reproductive Experiences Study. Am J Epidemiol 2011; 173: 38-47.
- Parker WH, Broder MS, Chang E, Feskanich D, Farquhar C, Liu Z, Shoupe D, Berek JS, Hankinson S, Manson JE. Ovarian Conservation at the Time of Hysterectomy and Long-Term Health Outcomes in the Nurses’ Health Study. Obstetrics and gynecology 2009; 113: 1027-1037.
- Carlson KJ. Outcomes of hysterectomy. Clin Obstet Gynecol 1997; 40: 939-946.
- Kreiger N, Sloan M, Cotterchio M, Kirsh V. The risk of breast cancer following reproductive surgery. Eur J Cancer 1999; 35: 97-101.
- Brinton LA, Schairer C, Hoover RN, Fraumeni JF Jr. Menstrual factors and risk of breast cancer. Cancer Invest 1988; 6: 245-254.
- Gaudet MM, Gapstur SM, Sun J, Teras LR, Campbell PT, Patel AV. Oophorectomy and hysterectomy and cancer incidence in the cancer prevention study-II nutrition cohort. Obstet Gynecol, 2014; 123: 1247-1255.
- Davelaar EM, Gerretsen G, Relyveld J. No increase in the incidence of breast carcinoma with subcutaneous administration of estradiol. Ned Tijdschr Geneeskd 1991; 135: 613-615.
- Wyrzykowski Z, Przyblyska B, Wyrzykowska K, Kaleczyc J. Influence of bilateral ovariectomy on the morphology and ultrastructure of the pineal gland in the pig (Sus scrofa)- quantitative and qualitative study. Folia Morphol (Warsz) 1992; 51: 93-108.
- Gerendai I, Banczerowski P, Halasz B. Functional significance of the innervation of the gonads. Endocrine 2005; 28: 309-318.
- Kuhn G, Hardegg W, Noack S, Trunk H. Long-term effects of hysterectomy and bilateral oophorectomy on lymphoid tissue in female Lewis rats. Vet Immunol Immunopathol 1991; 29: 353-363.
- Nemeth J, Tamas A, Jozsa R, Horvath JE, Jakab B, Lengvari I, Arimura A, Lubics A, Reglodi D. Changes in PACAP levels in the central nervous system after ovariectomy and castration. Ann N Y Acad Sci 2006; 1070: 468-473.
- Caruso D, Pesaresi M, Maschi O, Giatti S, Garcia-Segura LM, Melcangi RC. Effect of short-and long-term gonadectomy on neuroactive steroid levels in the central and peripheral nervous system of male and female rats. J Neuroendocrinol 2010; 22: 1137-1147.
- Amer MH. Genetic factors and breast cancer laterality. Cancer Manag Res 2014; 6: 191-203.
- Aareleid TP, Khint EK. O preobladanii opukholei v levoi molochnoi zheleze [About prevalence of tumors in the left breast]. Voprosy onkologii 1987; 33; 5:37-42.
- Tulinius H, Sigvaldason H , Olafsdóttir G. Left and right sided breast cancer. Pathol Res Pract 1990; 186: 92-94.
- Weiss HA, Devesa SS, Brinton LA. Laterality of breast cancer in the United States. Cancer Causes Control 1996; 7: 539-543.
- Perkins CI, Hotes J, Kohler BA, Howe HL. Association between breast cancer laterality and tumor location, United States, 1994-1998. Cancer Causes Control 2004; 15: 637-645.
- Sughrue T, Brody JP. Breast tumor laterality in the united states depends upon the country of birth, but not race. PLoS ONE 2014; 9: e103313.
- Bao J, Yu K-D, Jiang Y-Z, Shao Z-M, Di G-H. The effect of laterality and primary tumor site on cancer-specific mortality in breast cancer: a SEER population-based study. PLoS ONE 2014; 9: e94815..
- Zeeneldin AA, Ramadan M, Elmashad N, Fakhr I, Diaa A, Mosaad E. Breast cancer laterality among Egyptian patients and its association with treatments and survival. J Egypt Natl Canc Inst, 2013; 25: 199-207.
- Jones RE, Lopez KH, Maldonado TA, Summers TR, Summers CH, Propper CR, Woodling JD. Unilateral ovariectomy influences hypothalamic monoamine asymmetries in a lizard (Anolis) that exhibits alternation of ovulation. Gen Comp Endocrinol 1997; 108: 306-315.
- Ayala ME, Rosas P, Dominguez R. Different effects of unilateral and bilateral lesions of the dorsal raphe nucleus on puberty and first ovulation. Brain Res Bull 1994; 34: 27-30.
- Gerendai I, Csaba Zs, Voko Z, Csernus V. Effect of unilateral deafferentation in the medial basal portion of the temporal lobe on the hypophyseo-ovarian axis in rats: an age-dependent lateralized control mechanism. Brain Res 1993; 619: 173-179.
- Morales L, Ricardo B, Bolaños A, Chavira R, Domínguez R. Ipsilateral vagotomy to unilaterally ovariectomized pre-pubertal rats modifies compensatory ovarian responses. Reprod Biol Endocrinol 2007; 5: 24.
- Filippova EB, Bianki VL. Jeffekty gonadjektomii na mezhpolusharnuju asimmetriju krys [The effect of gonadectomy on interhemispheric asymmetry in rats]. Zh Vyssh Nerv Deiat Im I P Pavlova 1990; 40: 565-574.
- Bianki VL, Filippova EB. Sex differences in lateralization in the animal brain. CRC Press 2001.
- Gaignard P, Savouroux S, Liere P, Pianos A, Thérond P, Schumacher M, Slama A, Guennoun R. Effect of sex differences on brain mitochondrial function and its suppression by ovariectomy and in aged mice. Endocrinology 2015; 156: 2893-2904.
- Anbazhagan R, Gusterson BA. Reversed cerebral asymmetry and breast cancer. Lancet 1992; 25; 339: 1056.
- London WP. Reversed cerebral asymmetry and breast cancer. Lancet 1992; 339: 1055-1056.
- Klar AJ. Breast cancer predisposition and brain hemispheric laterality specification likely share a common genetic cause. Breast Dis 2011; 33: 49-52.
- Poroshenko AB. O prirode deficita protivorakovoj ustojchivosti organizma [About the nature of deficiency of antitumorogenic resistance of an organism]. Means and mechanisms of rising of antitumoral protection in oncology: collection of proceedings RNIOI. Ed. Sidorenko JS., Moscow 1993; pp 211-257.
- Balitsky KP, Veksler IG, Vinnitsky VB, Syromjatnikov AB, Shmal'ko JuP. Nervnaja sistema i protivoopuholevaja zashhita [Nervous system and antitumoral protection]. Ed. K.P. Balitsky, Kiev 1983. (In Russ.)
- Volegov AI. Ustojchivost' organizma k zlokachestvennym opuholjam [Fastness of an organism to malignant tumours]. Moscow Medicine 1987.