In this study, we demonstrate a relationship between weight variation during polychemotherapy treatment and both poorer disease-free survival and overall survival after diagnosis of breast cancer.
The present study is in agreement with previous studies which have found that overweight at the time of diagnosis increased both breast cancer recurrence and mortality. This result has been largely demonstrated in U.S. populations [25
]. The poorer prognosis of obesity at diagnosis could be explained by the fact that overweight women tend to be diagnosed with later stage cancer and therefore more adverse tumour characteristics than normal weight women [28
]. For some authors, this association is restricted to women who detected their own cancer and not spread amongst cases detected by either screening mammography or clinical breast examination [29
]. Additionally, lower screening rates may partly explain the higher breast cancer mortality in obese women [30
]. In agreement with this, in our population who were diagnosed 20 years ago, when no screening mammography was systematically carried out, we observed a striking association between BMI and tumour size.
In our series however, with a median WV equal to zero during chemotherapy treatment of breast cancer patients, 31% of our population presented a significant weight variation (> 5%) whereas 68% had maintained their weight. Our findings of no significant median WV during chemotherapy treatment are in contrast with the vast majority of studies conducted in North America, which have generally reported an average weight gain ranging from 1.7 to 4.4 kg during the years that follow diagnosis in women treated by chemotherapy [5
]. On the other hand, one study carried out in a Korean breast cancer population has already observed a lack of overall weight gain, with 10.4% of the population gaining more than 5% of baseline body weight at 1 year [31
]. Regarding the baseline mean BMI, we can observe that populations who did not display a significant weight gain during chemotherapy treatment, including ours, are leaner (mean BMI of 24.4 kg/m2 in our study, 23.5 kg/m2 in Korean study) than the ones used in the U.S. studies [5
] in which the mean BMI varied from to 26.3 to 27.4 kg/m2 [18
]. Moreover, one possible explanation is that the chemotherapy regimen administered to our patients incorporated anthracycline-based therapy as reported by Han and al. [33
], whereas the majority of the earlier previous studies that observed a weight gain, involved non-anthracycline-based regimen. Other retrospective and prospective reports have not demonstrated increased weight gain with anthracycline-containing regimens compared with other regimens [10
]. Fisher et al. [34
] noted that 14.4% of patients receiving treatment with the AC regimen gained ≥ 5% over pretreatment weight compared with 42.2% of patient receiving CMF. This result was comparable to our result (14% gained weight) indeed the fact that patient accrual took place prior to the widespread use of 5-HT3
receptor antagonists in the two studies (cancer-related treatment currently used to reduce the impact of nausea and emesis associated with anthracycline use).
The long-term follow-up of patients who received an anthracycline-based chemotherapy in this study demonstrates that weight variation may not only influence recurrence, but also patient outcome. In multivariate analysis, clinical node involvement was still significant, thus, weight change was the strongest parameter associated with OS and DFS in our series. Literature on prognostic value of weight variation is mixed and not easily comparable. These studies that generally evaluated post-diagnosis weight variation on different periods which varied from a few months to a few years after diagnosis, including different treatments (chemotherapy and or hormonotherapy, radiation only...), did not use the same prognostic outcomes, and sometimes with a short median of follow-up. Among the few studies which evaluated the prognostic value of weight change after breast cancer diagnosis, four studies have shown a poor prognosis [8
] whereas five reported no relationship [9
The majority of studies observed an impact of weight gain on patient outcome. The largest study to date included 5,204 Nurses' Health Study participants diagnosed with non-metastatic breast cancer between 1976 and 2000 treated with chemotherapy and/or hormonal therapy [14
]. This study reported an increased risk of recurrence, breast cancer death and total mortality in patients who gained more than 2 kg/m2
by comparison to patients who maintained their weight. However this relationship was found only among women who never smoked and the definition of recurrence included reported lung, bone or brain cancer, but excluded any local recurrences in the ipsilateral breast or new primaries in the contralateral breast. Camoriano et al. reported weight gain having a significant effect on overall survival during treatment with cyclophosphamide, fluorouracile and prednisolone (CFD) or CFD plus tamoxifen, but not on recurrence and this only for premenopausal women [8
]. Two other studies conducted prior the common use of anthracycline-based chemotherapy reported a correlation between weight gain and overall survival and/or disease-free survival (without defining which events were included) [15
Only one recent study reported some evidence that women with early stage breast cancer treated with chemotherapy and/or radiation and tamoxifen who had large weight loss (> 10%) were at higher risk of recurrence and death compared to women with no weight variation. This elevated risk was more pronounced among women who were obese before diagnosis or who had ER- or PR- tumours [19
]. One obvious explanation for significant weight loss being related to an increased risk of death could be that the breast cancer disease process itself caused weight loss.
Literature on the prognostic value of weight variation reported some evidence that women who had gained or lost weight have a higher risk of recurrence and death compared to women with no weight variation. So, we chose to group women who gained weight with those who lost weight as a weight changing group. We hypothesized that weight change reflected a metabolic disorder by comparison to women who maintained their weight with an energy balance in equilibrium (Figure ). Chemotherapy induced a decrease in energy expenditure (lowered basal metabolic rate, thermogenesis, and physical activity [4
]) and different modifications in dietary intake (increase in appetite [14
] or decreased ingestion of food due to chemotherapy related nausea and emesis) that can lead to weight gain or loss according to dietary behaviour of patient. Moreover, women with breast cancer receiving adjuvant chemotherapy underwent unfavourable changes in body composition with lean body loss due to a negative nitrogen balance [35
] even in the absence of an overall weight change [4
]. A lot of data has demonstrated that weight gain during chemotherapy was indicative of sarcopenic obesity [33
]. Indeed, chemotherapy for breast cancer like taxane and anthracycline can increase inflammation [36
] which played a central role on different modifications induced by chemotherapy. Inflammatory cytokines interfered with the satiety centre [38
] and catabolism of skeletal muscle protein responsive of sarcopenia but not independently of any of the considered obesity indexes [39
Possible mechanisms to explain weight change during chemotherapy treatment of non metastatic breast cancer and its prognostic value.
Several mechanisms have been proposed to explain the adverse effect of weight gain on risk of recurrence and mortality. First, weight gain and all associated metabolic disorders may predispose women to diabetes or heart disease, thereby predisposing them to morbidity and mortality [6
]. However, in our study, only a few patients died from causes other than breast cancer (14%). One possible mechanism was a greater aromatase activity in the excess adipose tissue [40
] and an inhibition of synthesis of sex hormone-binding globuline associated with an increased in free estradiol level which stimulates neoplasic cells [41
Insulin resistance may be a common mechanism to explain the poor prognosis of patients who experienced a weight loss or a weight gain (Figure ). Indeed, insulin resistance has been shown in variety of cancer patients with body-weight loss [42
], but was also seen in overweight women [43
]. Fasting serum insulin concentration has been directly associated with an increase in both distant recurrence and death in women previously treated for breast cancer [42
]. There is a strong biological rational for an adverse prognostic effect of insulin. Insulin, a member of a family of growth factors that includes IGF-I and IGF-II, exerts a mitogenic effect on malignant breast cancer cells though IGF-I receptor. It is also hypothesized that visceral obesity increases both insulin-like growth factors (IGF-I, IGF-II) which stimulates the synthesis of sex steroid hormones [31
] that are involved in the regulation of normal and malignant growth of epithelial breast cells. Several studies have reported a reduction in circulating concentration of IGF-I in malignant disease, which may also have been associated with nutritional decline and systemic inflammation [44
]. Yoshikawa et al. hypothesized that inflammatory reactions might be involved in the development of insulin resistance [42
]. Moreover, few studies reported an association between elevated inflammatory cytokines and a worse prognosis in breast cancer patients [45
Further research is needed to understand the biological mechanisms underlying the relationship between weight variation and breast cancer growth with exploration of insulin resistance in association with body composition, measurement of energy expenditures, calorie intake and inflammatory reaction.
The current study had several limitations including its study design (retrospective chart review) and a relatively small sample size to draw a conclusion on the independent effect of weight variation. Some interesting covariates like "normal " weight prior diagnosis, smoking status, physical activity or sociodemographic aspects (education) have not been explored because of the lack of this data in patients' medical records. Additionally, more detailed measurement of body shape and fat content are lacking. Currently a long-term measurement of weight during patient follow-up is ongoing and could offer the possibility to explore weight variation after treatment which could also affect prognostic outcomes.