By Author
  By Title
  By Keywords

July 2019, Volume 69, Issue 7

Research Article

Survival analysis of breast cancer patients with different treatments: a multicentric clinicopathological study

Saima Shakil Malik  ( Fatima Jinnah Women University, Rawalpindi )
Mehreen Baig  ( Surgical Unit, Fauji Foundation Hospital, Rawalpindi, Pakistan )
Muhammad Bilal Khan  ( Armed Forces Institute of Pathology (AFIP), Rawalpindi )
Nosheen Masood  ( Fatima Jinnah Women University, Rawalpindi )

Abstract

Objective: To explore and better understand clinic pathological details of breast cancer patients and analyse their survival rate among different treatment groups.
Methods: The prospective cohort, multi-centric study was conducted from September, 2014, to February, 2018, at five hospitals in Rawalpindi and Islamabad, Pakistan, and comprised histo-pathologically confirmed breast cancer cases. Patient characteristics and medical history were collected using a detailed questionnaire. All the subjects were followed up, and information regarding their current health and treatment status was collected. Data was analysed using SPSS 24.
Results: There were 347 subjects with a mean age of 44.3±12.2 years and body mass index of 27.9±4.0 kg/m2. Younger age, increased body mass index, consanguinity and family history were major contributing
factors in breast cancer development (p<0.05). Overall, 267(77%) had invasive ductal carcinoma and Grade II tumour 234(67%) was more frequent. A total of 221(64%) cases had positive lymph nodes and 97(28%) had metastasis to different body organs. Overall survival analysis showed statistically significant role (p<0.0001) of all treatment options.
Conclusion: Combination of different treatments can provide more promising health outcomes in breast cancer cases.
Keywords: Breast cancer, Risk factors, Treatments. (JPMA 69: .976; 2019)

Introduction

Breast cancer is not only the most commonly diagnosed malignancy among females, but also a leading cause of cancer-related deaths throughout the world.1 According to a report, Pakistan has the highest rate of breast cancer mortality and morbidity in Asia with 90,000 cases reported annually and more than 40,000 deaths. 2 Even then, its aetiology is not entirely explored yet. Breast cancer incidence and mortality varies tremendously among various ethnic groups and in different geographical locations. Once breast cancer was considered a disease of the Western women, but now Asians are also facing an alarming situation due to continuous increase in its incidence. It is obvious that increasing rate of breast cancer had damaging effect on public health and generated a burden on society as well. 3-5 Scientific knowledge has proved that breast cancer development is a multi-factorial  disease involving culture, lifestyle, environment and genetics. 6 Studies showed lower risk of breast cancer among immigrant Swedish women representing immense role of lifestyle in disease development. 7 Breast cancer risk fac tors var ied amon g premenopausal and postmenopausal Hispanic migrants as well. 8 Therefore, it was required to evaluate all the possible risk factors for a better understanding of breast cancer aetiology. Age is considered one of the most important risk factors in breast cancer incidence. Its incidence even in the young women also varied with ethnicity and race. Breast cancer was more common in white women aged over 45 years compared to blacks. However, black women aged under 35 years had more than two-fold chance of having invasive breast cancer and three-fold increased breast cancer mortality than young white women. 9-11 In the United States, about 7% of women were diagnosed with breast cancer before the age of 40 years. Older women face poor survival rates compared to the young ones and it was reported that younger age was an independent prognostic factor for adverse disease outcome. 12 Obesity was one of the growing health problems throughout the world. Being overweight meant that a woman had increased risk of postmenopausal breast cancer. Evidence also illustrated that it was associated with poor prognosis in patients diagnosed with earlystage breast cancer. Many studies suggested that patients who were obese at the time of breast cancer diagnosis were more prone to cancer recurrence and early death compared to the leaner ones. Even breast cancer patients who became overweight after diagnosis may also be at manifold increased risk of poor treatment outcomes. 13,14Menarche and menopause were basically markers of onset and termination of many endocrine-related activities associated with reproduction. Ovary produces steroid hormones, directly involved in the breast development and functioning. Both early menarche or late menopause were responsible for increased breast cancer risk as reported by a meta-analysis of the Collaborative Group on Hormonal Factors in Breast Cancer. 15,16Clinical and epidemiological data showed that increased breast cancer risk can be managed by different interventions in lifestyle, hormonal balance and surgery. Aromatase inhibitors and oestrogen receptor modulators could reduce the increasing burden of breast cancer in high-risk populations. 17 As demographic incidence of breast cancer had showed substantial difference between various populations, it merits in- depth investigation of breast cancer development and its associated risk factors. The current study was planned to investigate clinic pathological details of breast cancer patients, and to have a look at the survival rate of breast cancer patients undergoing different treatments.

Patients and Methods

The multi-centric, perspective cohort study was conducted at Shifa International Hospital, Islamabad, Holy Family Hospital, Rawalpindi, Benazir Bhutto Shaheed Hospital, Rawalpindi, District Headquarters Hospital (DHQ), Rawalpindi, and Combined Military Hospital (CMH), Rawalpindi, Pakistan, from September 2014, to February 2018. After obtaining approval from the institutional review boards of all the five hospitals and that of Fatima Jinnah Women University, Rawalpindi, the sample size was calculated with G power software18 taking 5% margin of error, hazard ratio 2 and with 80% power. 19 The calculated sample size was 82 but a greater sample size was targeted to increase study weightage and generalisability of theresults. All patients of breast cancer in the study hospitals were included, but those with missing data and those not willing to participate were excluded. Epidemiological and clinical details of the subjects were collected using a detailed questionnaire from the patients or their attendants and with the help of hospital records after taking written informed consent. Information collected included age, body mass index (BMI), marital status, consanguinity, menarche, menopause, number of pregnancies and children, age at first pregnancy, number of abortions, lactation history, family history, grade and treatment. Patients with BMI 18.5-22.9 kg/m2 were categorised as normal, 23- 24.9 kg/m2 overweight, 25- 29.9.9 kg/m2 obese class I, and more than 30 or above as obese class II as per World Health Organisation (WHO) classifications for Asians. 20 For survival analysis, patient's current status and treatment options were collected through telephonic calls. Patients were contacted after 6 months from the start of the study time and information regarding changes in their treatment was noted. If a patient had died in the intervening time, exact time of death was noted. Patients were divided into three different groups based on treatment, as (i) chemotherapy, (ii) chemotherapy and surgery, and (iii) chemotherapy, surgery and radiotherapy. Death due to any cause and was counted as censored cases in the survival analysis. Time used for survival analysis was basically time to shift from one treatment to the other. Data was analysed using SPSS 24. Breast cancer demographic factors, like age, BMI, age at menarche, ageat first full time pregnancy and number of live births, were expressed as mean and standard deviation. Frequencies and percentages were used to express marital status, consanguinity, menarche, menopause, lactation history, history of abortions, family history of breast cancer, histopathological grade, metastasis and treatments. Kaplan Meier test was used to measure progression-free survival among patients in the three treatment categories. Overall survival was defined as time interval from study entry to any event which was either change of treatment or death. Log rank (Mantel-cox) was used to find the significance of overall treatment. P<0.01 was taken as significant.

Results

Of the 421 patients initially approached, 41(9.7%) refused to participate and 33 (7.8%) were lost during follow-up. The final sample, as such, comprised 347 (82.42%) participants with a mean age of 44.3±12.2 years and BMI of 27.9±4.0 kg/m2. Overall, 19 (3.9%) patients were of normal weight, 64 (13%) overweight, 159 (32.3%) obese class I and 105(21.3%) were obese class II. Family history of breast cancer was found in 109 (31.4%) cases. Most of the cases 302 (87%) were married and among them 167 (55.3%) had consanguinity. Mean age of breast cancer cases at menarche was 12.1±0.8 years. Among the subjects, 89 (25.6%) were post-menopausal and 258 (74.4%) had not reached menopause at the time of data collection. Mean age at first full-term pregnancy was 21.3±3.9 years, and the mean number of live births was 4.6±1.9. Only 9(2.6%) cases were nulliparous and among the parous women, 11 (3.2%) had no lactating history. Among the breast cancer cases, 86 (24.8%) women had history of abortions. Overall, 267 (77%) patients had invasive ductal carcinoma and 80(23%) had invasive mammary carcinoma. Grade II tumour was found in 234 (67%) cases compared to grade III in 113 (33%) on the basis of histopathology. Positive lymph nodes were found in 221 (64%) cases. Metastasis to different body organs was observed in 97(28%) cases.In terms of treatment category, 103 (29.8%) patients were on chemotherapy, 231 (66.5%) had undergone surgery after chemotherapy, and 13 (3.7%) were on radiotherapy after chemotherapy and surgery. Overall, 270 (78%) patients were alive (Table 1).



Survival analysis showed positive trend of each therapy and there was a statistically significant role (p<0.0001) of all treatments (Table 2).



Trend of deaths in different treatments was also noted (Figure).



Discussion

Breast cancer is one of the most common types of cancer among females, and the leading cause of deaths across the world. The current study was conducted to evaluate the role of various risk factors in breast cancer development. At first it was thought that breast cancer was a disease of older age, but the incidence of disease below 40 years of age has become common today. Most of the breast cancer cases were among pre-menopausal women. In the current study, mean age of breast cancer c ases was 44. 3 years and most of them were premenopausal. Cases diagnosed at younger age possess aggressive clinicopathological characteristics and had exclusive biological entity. 1,4,12Obesity was a well-known risk factor in breast cancer development, particularly in postmenopausal women. According to an estimate, annual incidence of breast cancer could be reduced to half just by preventing obesity in the European Union. 21 Risk of breast cancer among obese women varies among different ethnic groups. Mean BMI reported in this study was 27.9 and most of the patients were obese representing an  association between obesity (fat accumulation) and breast cancer risk concordant with already reported results. 22,23 Breast cancer is a heterogenous disease both histologically and molecularly. It had distinct subtypes that varied in disease development, progression, response to treatment and disease-free survival. Diverse clinicopathological and  molecular tests were performed to assess disease progression, suggest most appropriate treatment and dosage regimes for breast cancer patients. Necessary information required for proper diagnosis and treatment includes age, family history, tumour size, lymph node status, histological grade, lymph vessel invasion, oestrogen (ER) / progesterone (PR) status, human epidermal growth factor receptor 2 (HER2) status, and evaluation of tumour margins. 24 In the current study, many patients had maternal history of breast cancer as reported in literature. Correlation exists between parity, consanguinity and age at first full-term pregnancy and is linked with increased breast cancer risk. 23,25 Chemotherapy was used in the treatment of early-stage invasive breast cancer, but in some cases, it was given before surgery as well to shrink cancer. Many of the breast cancer patients had undergone different types of surgeries during treatment. Radiotherapy was a highly targeted and effective procedure to kill cancerous cells. Cases enrolled in the current study had gone through all these treatments at different stages. Overall survival rate was good with combination of these treatments. Survival differences were not the only factor in selecting chemotherapy, surgery or radiotherapy for breast cancertreatment. Differences between these local therapies did not involve greater effects on 3.6-year survival, but there are chances of noticeable effects on long-term survival. 26,27

Conclusion

Age, BMI, marital status, consanguinity, menarche, menopause, number of pregnancies and children, age at first pregnancy, number of abortions, lactation history and family history contributed towards breast cancer development and may have been involved in disease progression as well. Overall survival analysis showed that different treatments conferred good impact on patient's survival and treatment alone was not responsible for increased breast cancer risk.

Disclaimer: The study is a part of a PhD thesis.
Conflict of Interest: None.
Source of funding: None.

References

1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018; 68: 7-30.
2. Shaheen N, Andleeb S, Naz F. Perceived Satisfaction with Social Support and Cancer Specific Psychological Stress in Newly Diagnosed Breast Cancer Women. Pakistan Journal of Social and Clinical Psychology. 2015;13: 72-9.
3. DeSantis CE, Bray F, Ferlay J, Lortet-Tieulent J, Anderson BO, Jemal A. International Variation in Female Breast Cancer Incidence and Mortality Rates. Cancer Epidemiol Biomarkers Prev. 2015; 24:1495- 506.
4. DeSantis CE, Fedewa SA, Goding Sauer A, Kramer JL, Smith RA, Jemal A. Breast cancer statistics, 2015: Convergence of incidence rates between black and white women. CA Cancer J Clin. 2016; 66: 31-42.
5. Torre LA, Sauer AM, Chen MS, Jr., Kagawa-Singer M, Jemal A, Siegel RL. Cancer statistics for Asian Americans, Native Hawaiians, and Pacific Islanders, 2016: Converging incidence in males and females.CA Cancer J Clin. 2016; 66:182-202.
6. Singletary SE. Rating the risk factors for breast cancer. Ann Surg. 2003; 237: 474-82.
7. Beiki O, Hall P, Ekbom A, Moradi T. Breast cancer incidence and case fatality among 4.7 million women in relation to social and ethnic background: a population-based cohort study. Breast Cancer Res. 2012;14: R5.
8. John EM, Phipps AI, Davis A, Koo J. Migration history, acculturation, and breast cancer risk in Hispanic women. Cancer Epidemiol Biomarkers Prev. 2005;14: 2905-13.
9. Althuis MD, Brogan DD, Coates RJ, Daling JR, Gammon MD, Malone KE, et al. Breast cancers among very young
premenopausal women (United States). Cancer Causes and Control. 2003;14:151-60.
10. Donovan M, Tiwary CM, Axelrod D, Sasco AJ, Jones L, Hajek R, et al. Personal care products that contain estrogens or
xenoestrogensmay increase breast cancer risk. Med Hypotheses. 2007; 68:756-66.
11. Shavers VL, Harlan LC, Stevens JL. Racial/ethnic variation in clinical presentation, treatment, and survival among breast cancer patients under age 35. Cancer. 2003; 97:134-47.
12. Anders CK, Johnson R, Litton J, Phillips M, Bleyer A. Breast cancer before age 40 years. Semin Oncol. 2009;36(3):237-49.
13. Ewertz M, Jensen MB, Gunnarsdottir KA, Hojris I, Jakobsen EH, Nielsen D, et al. Effect of obesity on prognosis after early-stage breast cancer. J Clin Oncol. 2011; 29: 25-31.
14. Ligibel J. Obesity and breast cancer. Oncology (Williston Park). 2011; 25: 994-1000.
15. Britt K. Menarche, menopause, and breast cancer risk. Lancet Oncol. 2012;13: 1071-2.
16. Cancer CGoHFiB. Menarche, menopause, and breast cancer risk: individual participant meta-analysis, including 118?964 women with breast cancer from 117 epidemiological studies. The Lancet Oncology. 2012;13: 1141-51.
17. Li F, Dou J, Wei L, Li S, Liu J. The selective estrogen receptor modulators in breast cancer prevention. Cancer Chemother Pharmacol. 2016; 77: 895-903.
18. Dean A, Sullivan K, Soe M. OpenEpi: Open source epidemiologic statistics for public health, version. 2014.
19. Abadi A, Yavari P, Dehghani-Arani M, Alavi-Majd H, Ghasemi E, Amanpour F, et al. Cox models survival analysis based on breast cancer treatments. Iranian journal of cancer prevention. 2014;
7: 124.
20. World Health Organisation(WHO), International Association for the study of obesity (IASO) and International Obesity Task Force (IOTF). The Asia Pacific Perspective : Redifining Obesity and its treatment. Geneva World Health Organisation, 2000 pp. 378-420.
21. Anderson AS, Key TJ, Norat T, Scoccianti C, Cecchini M, Berrino F, et al. European code against cancer 4th edition: obesity, bodyfatness and cancer. Cancer epidemiology. 2015; 39: S34-S45.
22. Simone V, D'Avenia M, Argentiero A, Felici C, Rizzo FM, De Pergola G, et al. Obesity and Breast Cancer: Molecular Interconnections and Potential Clinical Applications. Oncologist. 2016; 21: 404-17.
23. Gilani GM, Kamal S. Risk factors for breast cancer in Pakistani women aged less than 45 years. Ann Hum Biol. 2004; 31: 398-407.
24. Salhia B, Trippel M, Pfaltz K, Cihoric N, Grogg A, Ladrach C, et al. High tumor budding stratifies breast cancer with metastaticproper ties. Breast Cancer Res Treat. 2015; 150: 363-71.
25. Haber G, Ahmed NU, Pekovic V. Family history of cancer and its association with breast cancer risk perception and repeat mammography. Am J Public Health. 2012; 102: 2322-9.
26. Clarke M, Collins R, Darby S, Davies C, Elphinstone P, Evans V, et al. Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005; 366: 2087-106.
27. Grantzau T, Overgaard J. Risk of second non-breast cancer after radiotherapy for breast cancer: a systematic review and metaanalysis of 762,468 patients. Radiother Oncol. 2015; 114: 56-65.

Journal of the Pakistan Medical Association has agreed to receive and publish manuscripts in accordance with the principles of the following committees: