Background. Weight gain is found in patients with positive estrogen subtype breast cancer. The effect of weight gain on breast cancer recurrence is still being debated and associated with a poor prognosis. Being overweight is associated with an increase in estrogen production by adipose tissue.Methods. A retrospective and prospective cohort study with data collection was conducted from July 2018 - June 2019 at the outpatient unit of Dr. Sardjito Hospital. We reviewed medical records of patients who came from January 2013 - July 2018.  Three categories of weight gain:  weight loss, increase 0 - 5%, and increase > 5% from baseline will be evaluated.Statistical Analysis. The relationship between weight gain and some risk factors of recurrence was analyzed with cox regression and multivariate logistic regression tests. The Kaplan Meier method is used to show lifetime data.Result. Weight gain in breast cancer patients with positive Her2-negative estrogen receptor subtypes was not associated with recurrence (p = 0.264; HR 0.637; 95% CI 0.289 - 1.405). Patients with body mass index ≥ 25 kg / m2 at diagnosis had a lower risk of relapse than patients with body mass index < 25 kg / m2 (p = 0.026; HR 0.461; 95% CI, 0.234 - 0.912).Conclusions Weight gain after diagnosis in breast cancer patients with positive estrogen receptor-negative Her2 subtypes receiving hormonal therapy is not associated with recurrence

Hardianti, Mardiah Suci

Nugraha, Doddy Rizqi

Taroeno-Hariadi, Kartika Widayati

English

Acta Interna: The Journal of Internal Medicine

 Acta Interna The Journal of Internal Medicine, Volume 11, Number 1, June 2021: 32-38 32  The Effect of Weight Gain on Recurrence During Hormonal Therapy in Breast Cancer with Positive Estrogen Receptor and Negative Her2 Subtype  Doddy Rizqi Nugraha1, Kartika Widayati Taroeno-Hariadi2, Mardiah Suci Hardianti2 1Internal Medicine Residency Program, Department of Internal Medicine, Faculty of Medicine, Public Health and Nursing Universitas Gadjah Mada/Dr. Sardjito General Hospital 2Division of Hematology and Medical Oncology, Department of Internal Medicine, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada/Dr. Sardjito General Hospital ABSTRACT Background. Weight gain is found in patients with positive estrogen subtype breast cancer. The effect of weight gain on breast cancer recurrence is still being debated and associated with a poor prognosis. Being overweight is associated with an increase in estrogen production by adipose tissue. Methods. A retrospective and prospective cohort study with data collection was conducted from July 2018 - June 2019 at the outpatient unit of Dr. Sardjito Hospital. We reviewed medical records of patients who came from January 2013 - July 2018.  Three categories of weight gain:  weight loss, increase 0 - 5%, and increase > 5% from baseline will be evaluated. Statistical Analysis. The relationship between weight gain and some risk factors of recurrence was analyzed with cox regression and multivariate logistic regression tests. The Kaplan Meier method is used to show lifetime data. Result. Weight gain in breast cancer patients with positive Her2-negative estrogen receptor subtypes was not associated with recurrence (p = 0.264; HR 0.637; 95% CI 0.289 - 1.405). Patients with body mass index ≥ 25 kg / m2 at diagnosis had a lower risk of relapse than patients with body mass index < 25 kg / m2 (p = 0.026; HR 0.461; 95% CI, 0.234 - 0.912). Conclusions Weight gain after diagnosis in breast cancer patients with positive estrogen receptor-negative Her2 subtypes receiving hormonal therapy is not associated with recurrence.  Keyword. Breast cancer, weight gain, estrogen receptor, recurrence  Abstrak Latar belakang. Penambahan berat badan banyak ditemukan pada pasien kanker payudara subtipe estrogen positif. Efek penambahan berat badan terhadap kekambuhan kanker payudara masih menjadi perdebatan dan dikaitkan dengan prognosis yang buruk. Berat badan berlebih berkaitan dengan peningkatan produksi estrogen oleh jaringan adiposa.   Metode Penelitian. Kohort retrospektif dan prospektif dengan waktu pengambilan data Juli 2018 – Juni 2019 di poli Tulip RSUP Dr. Sardjito. Penelitian dilakukan dengan cara melihat rekam medis pasien yang berobat dari bulan Januari 2013 – Juli 2018. Akan dibandingkan pasien dengan penurunan berat badan, naik 0 – 5%, dan naik > 5% dari berat badan saat terdiagnosis Analisis Statistik. Hubungan penambahan berat badan dan beberapa faktor risiko terhadap kekambuhan dianalisis dengan cox regression dan uji regresi logistik multivariat. Untuk melihat kesintasan digunakan metode Kaplan Meier.  Hasil Penelitian. Penambahan berat badan pada pasien kanker payudara subtipe reseptor estrogen positif Her2 negatif tidak berhubungan dengan kekambuhan (p = 0.264; HR 0.637; IK 95% 0.289 – 1.405). Pasien dengan indeks massa tubuh ≥ 25 kg/m2 saat terdiagnosis memiliki risiko lebih rendah untuk kambuh dibandingkan pasien dengan indeks massa tubuh < 25 kg/m2 (p = 0.026; HR 0.461; IK 95%, 0.234 – 0.912). Simpulan. Penambahan berat badan setelah terdiagnosis pada pasien kanker payudara subtipe reseptor estrogen positif Her2 negatif yang mendapatkan terapi hormonal tidak berhubungan dengan terjadinya kekambuhan.  Kata Kunci. Kanker Payudara, estrogen positif, penambahan berat badan, kekambuhan  Nugraha et al. 33  Introduction Weight gain is commonly found in breast cancer patients. Patients experienced weight gain after being diagnosed or while undergoing therapy with a prevalence of 50% - 96%. Goodwin et al. showed that 84% of 535 breast cancer patients gained 1 year after being diagnosed with an average of 1.6 kg.1 The effect of weight gain on breast cancer recurrence is still being debated. Many researchers claim weight gain after diagnosis has poor prognostic factors, increasing the risk of recurrence and increasing the risk of death.2 Estrogen has a role in weight management. A study on mice that are blunted with alpha estrogen receptors shows metabolic syndrome profiles such as weight gain, increased visceral fat, and glucose intolerance dysregulation.3  In Indonesia, 52.1% of breast cancer patients express estrogen receptors and hormonal therapy with estrogen blockers as standard therapy.4 Tamoxifen is a selective estrogen receptor modulator. Tamoxifen administration for 5 years is a standard therapy in patients with pre-menopausal breast cancer positive hormone receptor subtypes, while patients who have experienced menopause can be given aromatase inhibitors as an alternative to tamoxifen or sequentially after tamoxifen.5 Tamoxifen is known to have side effects such as menopause symptoms, thromboembolism, endometrial cancer, and weight gain. A study showed that tamoxifen was associated with an increased incidence of diabetes in elderly breast cancer patients.6 The effect of weight gain after diagnosis on recurrence is not yet understood. Some of the hypotheses proposed include hormonal disorders, increased estrogen production, changes in the endocrine system, changes in the immune system, changes in activity levels, and psychological factors. Adipose tissue is an endocrine organ that can convert androgens into estrogens. In addition, adipose tissue also produces compounds that cause the progression of breast cancer such as leptin, adiponectin, and inflammatory cytokines.7 The study that shows the relationship between weight gain after diagnosis to recurrence and the study that evaluates the effect of hormonal therapy on weight gain is still controversial. In addition, it is important to know the independent risk factors that influence weight gain after being diagnosed. If weight gain after diagnosis, especially in breast cancer-positive estrogen receptor subtypes, is an indicator of a poor prognosis interventions as early as possible should be given to maintain weight. Methods This is a retrospective and prospective cohort study in the outpatient clinic of RSUP Dr. Sardjito. Data retrieval time is July 2018 - June 2019. The subjects were female breast cancer patients of pre-menopausal, postmenopausal age, age ≥ 18 years, positive estrogen receptor status, after undergoing surgery and receiving adjuvant chemotherapy or immediately given hormonal therapy for at least 12 months. Exclusion criteria: had chemotherapy and hormonal therapy outside RSUP Dr. Sardjito and double tumor.  Based on the calculation of the sample size formula for cohort studies, the minimum sample size is 154 subjects. Basic characteristics will be analyzed descriptively and 3 variations of weight gain using Chi-Square. To examine the relationship between several risk factors and recurrence, a univariate cox regression and multivariate cox regression analysis will be performed. Statistically, significant risk factors will be continued to a multivariate logistic regression test. Lifetime or survival can be obtained from the Kaplan Meier method.  Acta Interna The Journal of Internal Medicine, Volume 11, Number 1, June 2021: 32-38 34   Table 1. Baseline characteristic Baseline characteristic  Weight gain gain 0-5% gain >5% loss P N % N % N %  Age  52.7 ± 9.3 49.2 ± 9.6 51.4 ± 8.1 0.243 Education No school 0 0.0% 2 5.4% 0 0.0% 0.574 SD 11 28.9% 7 18.9% 8 19.0%  SMP 2 5.3% 4 10.8% 4 9.5%  SMA 9 23.7% 10 27.0% 8 19.0%  Bachelor 3 7.9% 2 5.4% 2 4.8%  Undergraduate 4 10.5% 6 16.2% 11 26.2%  N.A 9 23.7% 6 16.2% 9 21.4%  Occupation Housewife 12 31.6% 13 35.1% 11 26.2% 0.995 Retired 7 18.4% 6 16.2% 7 16.7%  Employees 4 10.5% 5 13.5% 5 11.9%  Entrepreneur 6 15.8% 6 16.2% 10 23.8%  Labor 5 13.2% 4 10.8% 4 9.5%  N.A 4 10.5% 3 8.1% 5 11.9%  Insurance JKN PBI 13 34.2% 13 35.1% 14 33.3% 0.690 JKN non PBI 25 65.8% 23 62.2% 28 66.7%  N.A 0 0.0% 1 2.7% 0 0.0%  Marital  status Married 34 89.5% 31 83.8% 35 83.3% 0.733 Single 0 0.0% 1 2.7% 2 4.8%  Divorced 4 10.5% 5 13.5% 5 11.9%  Menopause Pre menopause 18 47.4% 11 29.7% 14 33.3% 0.242 Post menopause 20 52.6% 26 70.3% 28 66.7%  BMI baseline Underweight 4 10.5% 5 13.5% 1 2.4% 0.590 Overweight 9 23.7% 10 27.0% 12 28.6%  Obese 5 13.2% 2 5.4% 5 11.9%  Ideal 20 52.6% 20 54.1% 24 57.1%  PR (%) Positive 28 73.7% 27 73.0% 30 71.4% 0.771 Negative 10 26.3% 10 27.0% 11 26.2%  N.A 0 0.0% 0 0.0% 1 2.4%  Tumor size T1 5 13.2% 6 16.2% 7 16.7% 0.537 T2 13 34.2% 16 43.2% 13 31.0%  T3 9 23.7% 10 27.0% 15 35.7%  T4 11 28.9% 5 13.5% 6 14.3%  N.A 0 0.0% 0 0.0% 1 2.4%  Nodes Positive 15 39.5% 14 37.8% 18 42.9% 0.939 Negative 22 57.9% 21 56.8% 23 54.8%  N.A 1 2.6% 2 5.4% 1 2.4%  Stage I 5 13.2% 4 10.8% 6 14.3% 0.905  II 19 50.0% 20 54.1% 20 47.6%   III 14 36.8% 13 35.1% 15 35.7%   N.A 0 0.0% 0 0.0% 1 2.4%  Result We reviewed the medical records of patients from January 2013 - July 2018. Based on the medical records, we obtained basic patient data, laboratory results, histopathological results, and imaging. Observation of the medical record found that patients with positive estrogen receptor subtypes and negative Her2 were 221 patients. We excluded 1 male sex patient, 9 Nugraha et al. 35  patients who came in with stage 4, and 11 patients with incomplete data.  Patients who enter the inclusion criteria are patients who have received hormonal therapy for at least 12 months. There were 83 patients who had not completed hormonal therapy for 12 months. The final sample is 117 patients (n = 117). Body measurements were carried out with a standard scale that had been calibrated. Patients also assessed progress status based on the results of examinations in the medical record. This study divides weight gain into 3 groups, patients with decreased body weight, a gain of 0 - 5%, and a gain of > 5%. Patients who experienced weight loss were 42 patients (35.9%), a gain of 0 - 5% were 38 patients (32.5%), and a gain of > 5% were 37 patients (31.6%). Table 1 shows the baseline characteristics of patients based on weight gain. According to the table, we obtained homogeneous characteristic data from the three weight gain groups (p> 0.05). The relationship between BMI to recurrence is shown in table 2. There are significant differences in overweight patients when compared with ideal BMI. Patients with a higher BMI at the time of diagnosis were a protective factor for recurrence compared to an Ideal BMI (p = 0.013; HR 0.352; 95% CI, 0.155 - 0.801). A total of 7 patients (22.6%) with overweight had a recurrence while 24 patients (77.4%) did not experience a recurrence.  Table 2. Cox regression analysis BMI to recurrence   Recurrence status         BMI Yes No p HR IK 95%   n % n %         Underweight 3 30.0% 7 70.0% 0.266 0.510 0.156 - 1.671 Overweight 7 22.6% 24 77.4% 0.013 0.352 0.155 - 0.801 Obese 4 33.3% 8 66.7% 0.443 0.665 0.235 - 1.885 Ideal 31 48.4% 33 51.6%      Table 3. Cox regression analysis BMI ≥ 25 kg/m2 compared to BMI < 25 kg/m2   Recurrence status       BMI Yes No p HR IK 95%   n % N %     ≥ 25 kg/m2 11 25.6% 32 74.4% 0.026 0.461 0.234 - 0.912 < 25 kg/m2 34 45.9% 40 54.1%      Patients with BMI ≥ 25 kg / m2 were 43 patients (36%) and patients with BMI <25 kg / m2 were 74 patients (64%). BMI ≥ 25 kg / m2 which relapsed 11 patients (25.6%) and 32 patients (74.4%) did not relapse. BMI < 25 kg / m2 that had recurred were 34 patients (45.9%) and 40 patients (54.1%) had no recurrence. After cox regression analysis, patients with BMI ≥ 25 kg / m2 became a protective factor against recurrence compared to patients with a normal BMI (p = 0.026; HR 0.461; 95% CI, 0.234 - 0.912). The relationship between weight gain during hormonal therapy is shown in Table 4. Weight gain is divided into 3 categories, weight loss, a gain of 0 - 5%, and a gain of > 5%. In this study, 42 patients (36%) experienced weight loss, weight gain 0 - 5% were 38 patients (32%), and  Acta Interna The Journal of Internal Medicine, Volume 11, Number 1, June 2021: 32-38 36   p = 0.118 Gain  > 5% Gain  0 – 5% Loss months progression free survival weight gain > 5% were 37 patients (32%). Patients who experienced recurrence were 45 patients (38%) and patients who did not experience recurrence were 72 patients (62%). After Cox regression analysis, patients who gained 0 - 5% were not related to recurrence when compared to patients who experienced weight loss (p = 0.331; HR 1.39; IK 95 % 0.715 - 2,706). Patients with weight gain > 5% were also not associated with recurrence compared with patients who experienced weight loss (p = 0.264; HR 0.637; 95% CI 0.289 - 1.405). Table 4. Cox regression analysis of weight gain to recurrence Weight gain Recurrence status         Yes No P HR IK 95% N % n %         Gain 0 - 5% 19 50.0% 19 50.0% 0.331 1.391 0.715 - 2.706 Gain > 5% 10 27.0% 27 73.0% 0.264 0.637 0.289 - 1.405 Weight loss 16 38.1% 26 61.9%      Based on weight gain, patients with weight gain> 5% have the longest free progression time of 5 years which is 50.7 months. Furthermore, patients who experienced weight loss had a 5 years progression-free survival for 38.2 months and patients with weight gain 0 - 5% had the shortest progression-free survival time for 43.5 months. But after the log-rank test, the result was statistically not significant with p = 0.118.               Figure 1. 5-year progression-free survival based on weight gain There are confounding factors that can affect recurrence. These factors include menopause, tumor size, involvement of lymph nodes, and cancer stage. Surgery and radiotherapy are factors that affect recurrence. However, in this study, all research samples had been surgically removed and radiotherapy. Table 5 explains the factors that influence recurrence in this study. Variables that can be continued to multivariate analysis are variables with a value of p <0.25. Nugraha et al. 1   Table 5. Cox regression analysis variables that correlated to recurrences Variable p HR IK 95% Menopause 0.312 1.361 0.749 – 2.474 Tumor size 0.736 0.991 0.939 – 1.046 Nodes 0.542 0.994 0.973 – 1.014 Stages 0.676 0.985 0.915 – 1.095 BMI ≥ 25 kg/m2 0.026 0.461 0.234 - 0.912 Weight gain 0.331 1.391 0.715 – 2.706  On Table 5, only BMI ≥ 25 kg / m2 with a value of p <0.25 (p = 0.026). In conclusion, BMI ≥ 25 kg / m2 is an independent factor with a lower risk of recurrence compared to patients with BMI < 25 kg / m2 in this study.  Discussion A total of 117 subjects in this study had baseline characteristics that were not significantly different. Including several confounding factors that affect recurrences such as lymph node involvement, tumor size, or tumor stage. So, it can be concluded that the subjects of this study are homogeneous. Breast cancer-positive estrogen receptor subtypes with Her2 negative (luminal A and luminal B / Her2 negative) have the best 5-year progression-free survival time of 92.2% (95% CI, 90.5 - 93.9). This type of breast cancer has the best prognosis compared to the Her2 and basal (triple negative) subtypes. In the ATLAS study the administration of tamoxifen hormonal therapy > 10 years had a low risk of recurrence of 21.4% (RR 0.75; 95% CI, 0.62 - 0.9) and 25.1% (RR 0.90; 95% IK, 0.79 - 1.02; p = 0.002) at patients who received tamoxifen for 5 - 9 years.8 In this study, overweight patients (p = 0.013; HR 0.352; 95% CI, 0.155 - 0.801) and BMI ≥ 25 kg / m2 became a protective factor against recurrence compared to BMI < 25 kg / m2 at first times diagnosed (p = 0.026; HR 0.461; 95% CI, 0.234 - 0.912). Overweight patients had better progressive free survival time for 5 years than those with thin, normal, or obese but were not significant (p = 0.053). However, there was a significant difference in 5-year progression-free survival time in patients with BMI ≥ 25 kg / m2 compared with patients with BMI < 25 kg / m2. Patients with BMI ≥ 25 kg / m2 had longer progression-free survival (51.4 months) compared with patients with BMI < 25 kg / m2 (45.1 months) (p = 0.021). The results of this study differ from previous studies which stated overweight, or obesity had lower survival. Obese breast cancer patients have a large tumor size with lymphatic vessel invasion and have significantly lower progression-free survival. But this happens in the triple-negative subtype. Whereas in the positive estrogen receptor subtype, there was no significant difference in progression-free survival based on BMI. In addition, this can be due to differences in the efficacy of hormonal therapy, especially in postmenopausal patients.9 In this study, weight gain did not affect recurrence. Both patients with weight gain 0 - 5% (p = 0.331; HR 1.39; 95% CI 0.715 - 2.706) or gained weight > 5% (p = 0.264; HR 0.637; 95% CI 0.289 - 1,405). 5 years of progression-free survival there was no significant difference in the three categories of weight gain (p = 0.118). Studies about the effect of body weight, weight gain, and BMI on breast cancer patients with  Acta Interna The Journal of Internal Medicine, Volume 11, Number 1, June 2021: 32-38 38  positive estrogen receptor subtypes on recurrence are still limited. One of them is research by Dignam. According to Dignam, recurrence in breast cancer patients receiving tamoxifen therapy is not affected by body weight or BMI. The results of Dignam's study show there was no statistical difference between obese or thin/normal patients who received tamoxifen for the recurrence of breast cancer (p = 0.96; HR 1.52; 95% CI, 0.77 - 2.03). Besides, weight / BMI does not affect the efficacy of tamoxifen. Statistically reduced relapse rates in patients receiving tamoxifen therapy were also not affected by body weight or BMI (p = 0.34).10  Conclusion Weight gain after diagnosis in breast cancer patients with Her2 negative estrogen receptor-positive subtypes receiving hormonal therapy is not associated with recurrence.  References 1. Goodwin P, Ennis M, Pritchard K, et al. Adjuvant treatment and onset of menopause predict weight gain after breast cancer diagnosis. J Clin Oncol. 1991;17(1):120–129. 2. Kroenke CH, Chen W, Rosner B, et al. Weight, weight gain, and survival after breast cancer diagnosis. Journal of Clinical Oncology. 2005;23(7):1370–1378. 3. Frank A, Brown L, Clegg D. The role of hypothalamic estrogen receptors in metabolic regulation. North. 2008;29(10):1883–1889. 4. Aryandono, T. Faktor Prognosis Kanker Payudara Operabel di Yogyakarta. Disertasi. Pasca Sarjana Universitas Gadjah Mada; 2006. 5. Khambri, D. Peran terapi hormonal pada kanker payudara. Majalah Kedokteran Andalas. 2015: 38(1). 6. Lipscombe LL,  Fischer HD,  Rochon PA. Association between tamoxifen treatment and diabetes. 2012:2615–2622. 7. Miyoshi, Y. Association of serum adiponectin levels with breast cancer risk. Clin. Cancer Res. 2003;9:5699–5704. 8. Burstein HJ, Prestrud AA, Seidenfeld J, et al. American Society of Clinical Oncology clinical practice guideline: update on adjuvant endocrine therapy for women with hormone receptor-positive breast cancer. J Clin Oncol. 2010;28:3784–3796 9. Turkoz FP, Solak M, Petekkaya I, Keskin O.  The prognostic impact of obesity on molecular subtypes of breast cancer in premenopausal women. Journal of B.U.ON., 18(2); 2013. pp. 335–341. 10. Dignam JJ, Wieand K, Johnson K. Obesity, tamoxifen use, and outcomes in women with estrogen receptor – positive early-stage breast cancer. 2017;95(19). 

The Effect of Weight Gain on Recurrence During Hormonal Therapy in Breast Cancer with Positive Estrogen Receptor and Negative Her2 Subtype

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The Effect of Weight Gain on Recurrence During Hormonal Therapy in Breast Cancer with Positive Estrogen Receptor and Negative Her2 Subtype

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