Obezitatea şi cancerul de sân

Introduction

Breast cancer is the leading cause of mortality in women worldwide and also in Romania. According to the data published by IARC (International Agency on Cancer Research), 781 deaths due to breast cancer in postmenopausal patients are due to obesity, thus ranking 26^th in the world⁽¹⁾. In 2013, the rate of breast cancer mortality in women was 116.3 per 100.000⁽²⁾.

Data published by World Health Organization (WHO) claim that 51% of adults over the age of 20 years old are overweight and 19% are obese⁽³⁾. Of these, 49.1% of women are overweight and 21.2% are obese. It is estimated that, by 2030, in Romania, 15% of men and 10% of women will be diagnosed with obesity.

In literature there are several risk factors of breast cancer mentioned, such as: genetic predisposition, hormonal factors, diet and lifestyle, benign breast disorders, breast density and environmental factors.

Of these risk factors, we consider the modifiable factors extremely important. One example is obesity, which is in turn influenced by diet, lack of physical activity, as well as hormonal factors.

In the European guideline for breast cancer treatment, it is emphasized that the accumulation of excess adipose tissue and reduced physical activity are detrimental to these patients⁽⁴⁾.

Given the physical, mental and socioeconomic impact that the diagnosis, treatment and monitoring of breast neoplasm bring for both diagnosed patients, their family and for the whole society, we consider it essential to identify and understand especially the modifiable risk and prognostic factors.

The problem of patients with a history of breast cancer includes many aspects related to both this diagnosis and the adverse effects determined by the treatment of this disease. Thus, these patients are evaluated periodically for the purpose of early detection of a possible recurrence (a risk that persists sometimes for several decades from diagnosis), of another neoplasm (at the level of the contralateral breast or with other location), as well as for the management of the adverse effects in the short or long term. Apart from these central problems, there are also psychosocial, genetic, fertility and family planning, as well as socioeconomic aspects.

When diagnosing a patient with breast cancer, the main question that arises is related to the means that could be used to improve the prognosis of these patients both in the short and long term. It appears that frequent imaging and biological monitoring of patients diagnosed and treated for breast neoplasm did not bring overall survival benefit⁽⁵⁾. What appears to be beneficial in reducing the risk of recurrence and mortality of patients with breast cancer is the sustained physical effort, weight loss, and obesity avoidance, as well as decreased alcohol consumption^(6,7).

Breast cancer is one of the neoplastic diseases influenced by excess adipose tissue, along with prostate, colon, rectal and endometrial neoplasm. In patients diagnosed with breast neoplasm, they may be overweight or obese at diagnosis, when this could also be considered a risk factor for them, or they accumulate excess adipose tissue after diagnosis in the context of various types of treatments (chemotherapy, hormone therapy).

The ways in which excess adipose tissue, respectively overweight and obesity influence the evolution of the breast neoplasm are multiple and complex.

According to a review published in September 2007 that followed 62 studies, a reduction in the risk of developing breast cancer with the practice of physical activity was highlighted in 47 (76%) of them, with an average risk reduction of 25% and 30%. A more important impact on reducing the risk of developing breast neoplasm has been observed in some cases, such as: recreational physical activity, sustained physical activity throughout life, intense physical activity in postmenopausal women, normoponderal women, hormone receptor negative tumors, women without family history of breast cancer and those who gave birth^(8,9).

According to a study published by Petrelli, up to 18,000 deaths due to breast cancer could be avoided if the patients remained normal weight throughout life.

In the prospective CANTO cohort study, in which 5098 patients were diagnosed with breast cancer, it was found that 19.2% were obese at diagnosis, 20.3% at one year, and 20.9% at two years after the diagnosis⁽¹⁰⁾. These data are important to consider that excess adipose tissue might be considered as an important risk factor, but also that breast cancer once diagnosed and treated specifically (chemotherapy, hormone therapy) could favor overweight in these patients.

Several points of interaction and interdependence between evolution of breast neoplasm and excess of adipose tissue have been described. The following will detail the main ways in which obesity influences the evolution of breast neoplasm.

Molecular mechanisms activated by excess adipose tissue involved in the evolution of breast cancer

A significant number of molecules involved in intra- and intercellular signaling secreted by adipose tissue have been identified, involved in the genesis and evolution of breast neoplasm.

Adipose tissue and adipokines secreted by it appear to play an important role in the biology of breast neo­plasm. Leptin is one of the representative adipokines, which plays a key role in the migration of vascular endothelial cells, in angiogenesis and in the “harvesting” of macrophages and monocytes which in turn will secrete vascular endothelial growth factors and proinflammatory cytokines. Leptin also acts by stimulating angiogenesis, stimulating neoangiogenesis and contributing to breast carcinogenesis⁽¹¹⁾. Obesity is characterized by hypertrophy of adipose cells, which causes the appearance of hypoxic areas, hypoxia being a well-known factor in stimulating neoangiogenesis, cellular motility and invasion. In neoplastic pathology, mammary leptin and its receptor can be activated in response to hypoxia and hyperinsulinemia⁽¹²⁾.

A meta-analysis which looked at 23 clinical studies revealed that an increased serum leptin level was associated with an increased risk of developing breast cancer⁽¹³⁾.

The relationship between adipose tissue and carcinogenesis, especially in breast neoplasm, may be conditioned by changes in the leptin-adiponectin ratio. As the adipose tissue deposit increases, the difference between the serum levels of the two adipokines increases, respectively the leptin level increases and the adiponectin level decreases. A low adiponectin-leptin ratio increases the risk of breast cancer. According to some studies, it seems that weight loss by reducing caloric intake seems to cause a decrease in serum leptin concentration and an increase in serum adiponectin concentration⁽¹⁴⁾. Some authors also argue for the role of low-fat diet in altering the leptin-adiponectin ratio⁽¹⁵⁾.

It seems that adiponectin, this multifunctional protein, by increasing the serum level has a protective role against the development of various types of pathologies associated with diabetes: metabolic syndrome, diabetes, cardiovascular diseases or neoplasms⁽¹⁶⁾. Increased serum levels of adiponectin and increased receptor expression for adiponectin correlated with a smaller tumor size in breast cancer⁽¹⁷⁾.

Insulin, insulin-like growth factor 1 (IGF-1), and insulin resistance are frequently involved in the proliferation of neoplastic tissue. By the fact that this hormone interacts with so many signaling pathways after binding to its receptor, insulin, in addition to its role in energy metabolism, has an important function in transmitting growth and proliferation signals through its interaction with the mitogen-activated protein kinase (MAP) signaling pathway⁽¹⁸⁾.

Due to the fact that insulin plays a key role in lipid and protein metabolism, as well as its interaction with other mediators of cell proliferation (insulin-like growth factor 1 and 2), this hormone is involved in cell growth.

Malignant cells at the level of the breast epithe­lium present an overexpression of insulin and insulin-like growth factors up to 10 times higher compared to normal cells. This overexpression can lead to an acceleration of cell proliferation in the presence of hyperinsulinemia.

Hyperinsulinemia causes an increase in IGF-1 and reduces the synthesis of IGF-binding globulin, which induces a significant increase in IGF-1 that will essentially bind to its insulin-like growth factor receptor type 1 (IGF-R1). The constitutive activation of this receptor will lead to the hyperactivation of mitogen-activated protein kinase (MAPK) signaling pathways and of the phosphatidylinositol – Akt – mTOR, whose role in cancer evolution is well known. Another mechanism of action of hyperinsulinemia is a decrease in the synthesis of estrogen-binding protein by the liver which leads to an increase in plasma estrogen and thus to an increased risk of developing breast cancer⁽¹⁹⁾.

Estrogen plays a key role in the development and progression of breast cancer, as evidenced by numerous studies⁽²⁰⁾.

The role of leptin in the development of breast neoplasm in women with obesity is illustrated in studies by S. Catalano which showed an increase in the aromatization of androgens (androstenedion and dehydroepiandrosteron) present in breast tissue, thus increasing the level of estradiol. This process occurs both in the adipose tissue and in the neoplastic cells, thus increasing up to 10 times higher in estrogen concentration in the tumor microenvironment compared to the serum concentration⁽²¹⁾.

A study published by Folkerd and co-workers demonstrated the correlation between BMI (body mass index) and serum estradiol and estrone sulfate levels in postmenopausal women with positive estrogen receptor at immunohistochemistry⁽²²⁾. A review of the specialty literature by S.J. Ioannides and co-workers highlighted that obesity had an adverse effect on the efficacy of aromatase inhibitors⁽²³⁾. Another mode of action of leptin is to decrease the ubiquitination of the estrogen receptor alpha and thus reduce the efficacy of hormonal treatment in breast cancer⁽²⁴⁾.

The pathophysiology and molecular mechanisms involved in the connection between adipose tissue and breast cancer, although not yet well understood, seem to involve three systems, as follows: steroid sex hormones, adipokines, and IGF-1.

When adipocytes do not receive enough oxygen, the transcription factor HIF-1 (hypoxia inducible factor-1) is activated, which generates a number of negative effects: inhibition of adiponectin production, insulin resistance, the production and release of proinflammatory cytokines and some angiogenetic factors that play a role in increasing vascularity, as well as increasing the production of free radicals. HIF-1 is involved in the regulation of transcription of some genes involved in carcinogenesis⁽²⁵⁾.

Obesity – a negative prognostic factor in breast cancer

A meta-analysis of 82 clinical studies published in 2014 in the Annals of Oncology showed, by tracking more than 200,000 patients diagnosed and treated for breast neoplasm, the fact that patients with a high body mass index had a poor survival compared to the normal-weight ones. An increase in both the mortality caused by breast neoplasm and the overall mortality was observed. Thus, patients with obesity compared with those of normal weight had a 41% higher risk of general mortality before diagnosis, 23% higher at less than one year after diagnosis and, respectively, a 21% higher risk one year after the diagnosis. What is very interesting is that this increase in mortality was not influenced by menopausal status, nor by the presence or absence of estrogen and progesterone receptors on immunohistochemistry⁽²⁶⁾.

A study published by M. Protani in 2010 showed an increase in both gender and breast cancer mortality by 33% in patients with obesity compared with those who were normal⁽²⁷⁾.

A recently published British prospective study (POSH) that followed the evolution of 2956 patients under the age of 40 years old, diagnosed with breast neoplasm in the period 2001-2007, demonstrated the negative impact of obesity on overall survival⁽²⁸⁾.

Impact of excess adipose tissue on the efficacy and toxicities of various types of treatment

The way in which obesity influences the prognosis of patients diagnosed with breast cancer is, of course, influenced by the fact that these patients do not receive optimal treatment due to excess adipose tissue. Thus, sometimes these patients do not have immediate access to certain imaging investigations or radiotherapy due to the unavailability of devices adapted to their weight.

Another very important aspect is related to morbidity and complications of post-mastectomy with or without reconstructive per primam, which for this category of patients appear with a higher frequency and appear to be difficult to manage. These complications include: wound/prosthesis dehiscence, infections, sepsis, deep vein thrombosis or pneumonia^(29,30).

Adjuvant radiotherapy after conservative breast surgery in overweight and obese patients causes more severe late adverse effects and poor cosmetic appearance⁽³¹⁾.

Calculating the optimal dose for chemotherapy is an impediment to this method. A retrospective study by the International Breast Cancer Study Group found that obese patients treated with chemotherapy who received a dose below 85% of the optimal dose had an increased rate of the recurrences⁽³²⁾. The recommendations of the American Society of Oncology (ASCO) consist in avoiding unjustified reduction of chemotherapy doses in obese patients, especially when the purpose of treatment is curative⁽³³⁾.

Chemo-induced amenorrhea itself is a predictive factor of response to treatment. A study conducted by Mehta showed that 71% of obese patients became amenorrhoeic after chemotherapy compared with 81% of patients who were not affected by obesity. K. Altun­dag and co-workers proposed a hypothesis that obesity, by suppressing chemotherapy-induced amenorrhea, is a poor prognostic factor for premenopausal patients⁽³⁴⁾.

A review of the specialty literature by S.J. Ioannides and co-workers highlighted that obesity had an adverse effect on the efficacy of aromatase inhibitors⁽²³⁾. Another mode of action of leptin is to decrease the ubiquitination of the estrogen receptor alpha and thus reduce the effectiveness of hormone treatment in breast cancer.

Practical considerations

Patients diagnosed with breast cancer represent a separate category of patients due to the impact represented by this diagnosis. These patients receive a difficult diagnosis to accept, as breast cancer is known to be responsible for a significant percentage of mortality in the population. Besides the impact determined by the severity of this diagnosis, another very important aspect is the psychic impact related to a possible threat of the integrity of one’s own image, considering the very important role that this organ has as a symbol of femininity and motherhood.

Excess adipose tissue often involves the presence of large breasts, on which the maneuvers of autopalpation and detection of a possible tumor formation have a reduced efficiency. Thus, these patients are most often diagnosed with larger tumors and axillary adenopathies compared to normal-weight patients. As a result, sometimes the prognosis of these patients is affected by a late diagnosis.

A particularly important aspect should be the assessment of body mass index when we initially evaluate patients with breast cancer. During this consultation, we should consider all the particular aspects related to the treatment and the possible complications that could arise for this category of patients, but also strategies regarding the possible measures that should be taken for weight loss.

Obesity has a significant influence on all therapeutic sequences.

Surgery – especially radical mastectomy with axillary lymphadenectomy with per primam or later reconstruction – is more often grafted by complications such as infections, delayed scarring, hemorrhage or perioperative thrombosis. The risk of developing lymphedema and its severity are significantly higher in patients with a body mass index greater than 30 kg/sqm.

Postoperative radiotherapy through the increased tegumental volume exposed to radiation in obese patients, as well as by decreasing the capacity to repair the damaged tissues, causes an increase in the rate of post-radiotherapy complications, as well as a reduction in the aesthetic appearance. Another important aspect in developing countries due to the small number of centers where this treatment can be administered, as well as the use of older technical means, is that some radiotherapy devices are not adapted to the weight of these patients which leads to the delay of the treatment until obtaining an available place where there are technical devices adapted to obese patients.

The efficacy of chemotherapy in this category of patients is influenced by the tendency to underdose treatment in current clinical practice, contrary to the recommendations from current specialty guidelines.

Chemotherapy can also promote the accumulation of excess adipose tissue and change body composition in favor of fat accumulation in patients who were initially normoponderal. It seems that an increased body mass index represents a negative prognostic factor independent of the type of chemotherapy administered⁽³⁵⁾.

Because a very current approach to establishing adjuvant treatment of patients diagnosed with early breast neoplasm is represented by the use of the Oncotype DX genetic recurrence score, an important question that arose was whether obesity and metabolic syndrome in patients with breast neoplasm were associated with a higher recurrence score⁽³⁶⁾. At the moment, there are not enough data in this regard, but it seems that for this group of patients the genetic recurrence score is not correlated with the presence of obesity or metabolic syndrome.

Hormone therapy is an essential part of reducing the risk of recurrence in patients with breast cancer with estrogen receptors present in immunohistochemistry. It seems that hormonal treatment is less effective in obese patients.

Hormone therapy, and especially the combination of LhRh analogue in premenopausal patients, is also responsible for the weight gain in these patients. This consequence of the treatment should be discussed with the patients before its initiation, both in order to ensure their optimum compliance with these treatments, but also to be able to take into account all the measures to avoid overweight if they are needed during the course. Sustained physical activity should always be encouraged in patients diagnosed with breast cancer.

The follow-up of patients after the diagnosis of breast cancer is complex. In case of patients with obesity and metabolic syndrome, it must be personalized, a very important aspect being their advice and encouragement to follow a healthy lifestyle with regular physical activity and avoiding the complications related to metabolic syndrome and obesity.

In the context of implications that the excess of adipose tissue has in the evolution and prognosis of the breast neoplasm, numerous clinical trials are being carried out in order to establish the impact of active support through different types of telephone interventions for improving the prognosis of these patients.

One of the most important studies in this regard is represented by ENERGY feasibility study (The Exercise and Nutrition to Enhance Recovery and Good Health for You), which enrolled 693 overweight or obese patients diagnosed with localized breast cancer during a four-year period. These were randomized in different groups and were applied a cognitive-behavioral therapeutic strategy by telephone and by correspondence, in order to obtain the weight loss and to improve the quality of life. The results regarding the improvement of survival without disease progression and regarding the quality of life are in progress⁽³⁷⁾.

Conclusions

Because the prevalence of obesity is constantly increasing and represents a very important health problem, the various types of pathologies associated with it and the impact that the excess of adipose tissue has on their evolution must be actively monitored.

Breast neoplasm is the leading cause of mortality among women, with a high degree of morbidity and disability for patients with advanced disease.

The mlecular mechanisms involved in the evolution of breast neoplasm in obese patients are complex and yet insufficiently deciphered.

Risk factors related to behavior, environment, occupational, as well as metabolic risks are responsible for more than one third of DALY (disability adjusted life years) – the number of healthy life years lost due to disability and poor health. Therefore, these causes can be prevented.

Numerous preclinical and clinical studies are underway to improve the prognosis of patients diagnosed with overweight and breast neoplasm.

Conflict of interests: The authors declare no conflict of interests.