Progression free survival in Iraqi breast cancer patients treated with adjuvant 3D conformal radiotherapy: A cross-sectional study

Introduction

Breast cancer is a common cancer in women, and it is estimated that one in eight women in the US will develop it in their life¹. It is the leading cancer among women in both Europe and the US and has become an emerging disease in developing countries^2,3. In Iraq, 3845 patients were estimated to have breast cancer in 2011⁴. Therapy requires a multidisciplinary team involving surgeons, medical oncologists, radiation oncologists, pathologists, radiologists, and supportive care personnel¹. Adjuvant radiotherapy decreases locoregional relapse, increases survival and palliates symptoms; after breast-conserving surgery (BCS), it is an essential component of treatment¹. In oncology, progression free survival (PFS) referred to the length of time during and after the treatment of a cancer, that a patient lives with it but it does not get worse and refers to situations in which a tumor is present, as demonstrated by laboratory, radiology, and/or clinical evidence⁵. In developing countries, survival rates are poorer than those in developed countries⁶. Approximately 30% patients with early-stage cancer develop metastases, whereas metastatic breast cancer occurs in 6 – 7% of newly diagnosed patients⁷. The 5-year survival rate with metastasis is 25%, and the overall survival (OS) is reported to be 24 months⁸. Adjuvant radiotherapy reduces the incidence of locoregional recurrence from 30% to 10.5% at 20 years and decreases deaths by 5.4% at 20 years⁹.

This study aimed to assess PFS in patients treated by hypofractionated three-dimensional conformal radiotherapy (3DCRT) and correlate PFS with patients' clinical and pathological profiles.

Methods

Results

Relapse patterns

Relapse occurred in 35 (11.7%) women, while the reminder (264, 88.3%) were non-relapsed (Table 1). The waiting period from last cycle of chemotherapy to the date of starting radiotherapy in weeks of this study had median 17 weeks and mode about 9 weeks, which ranged from 4 to 30 weeks (Figure 1).

Figure 1. Waiting period (weeks) between last cycle of chemotherapy and date of radiotherapy.

PFS in this study presented in 264 women, while relapsing was evident in 35 cases. Chest wall relapse occurred in 9 patients (25.7%). Other relapses included liver metastasis, bone secondaries, axillary LN relapse, lung metastasis and supraclavicular LN in 8 (22.9%), 6 (17.1%), 5 (14.3%), 4 (11.4%), 3 (8.6%) patients, respectively (Figure 2).

Figure 2. Relapsing pattern presented in the study participants (n=299).

The luminal A subtype relapsed in 69% of patients which represented major subtypes reliable for relapse, while HER2 enriched and triple negative subtypes occurred in 14% patients for both and 3% for luminal B (Figure 3).

Figure 3. Molecular subtypes in relation to relapsing status (n=293).

Progression free survival

Kaplan Meier survival curve estimation of PFS is shown in Figure 4. The PFS rates for relapse were 35 (11.7%) versus 264 (88.3%) for non-relapse, estimated using this curve, which indicated that when a woman received adjuvant radiotherapy, she was about nine times more likely to survive beyond the time than someone who did not receive adjuvant radiotherapy. The follow-up period was 12 months; the Kaplan Meier estimates of PFS for all the patients was censored at 9 months and the last was at 35 months. There was a trend for better PFS in patients receiving adjuvant radiotherapy, so radiotherapy was significantly associated with prolonged PFS.

Figure 4. Kaplan Meier survival curve of progression free survival in the study.

Discussion

In the present study, the age of patients was 25–75 years with a mean± standard deviation of 49.9±10.99 years, with the majority of patients in the group of 46–55 years (115, 38.5%). This is similar to the results of previous studies conducted in Iraq: Al-Rawaq et al., 2016¹⁴, Al-Khafaji et al., 2010¹⁵, and Al-Naqqash et al., 2009¹⁶. Age represents an important factor both for occurrence and management of breast cancer¹⁷. In our study, the median age of onset was > 10 years younger than that shown in studies in Europe and North America¹⁸. It has been proposed that these differences are due to differences in exposure to hormones, diet, physical activities, and other risk factors¹⁷. In most Arabian countries, breast cancer is commonly diagnosed in women younger than 50 years, which is consistent with the findings of our study, unlike in the US, where women aged 50 years and older are most commonly affected¹⁸.

The molecular subtype plays an important role in follow-up survival and prognosis in breast cancer. Luminal A (67.2%), luminal B (11.6%), triple-negative (11.3%), and HER2-enriched (9.9%) subtypes were observed in the present study. These results are similar to those found in Cheang’s study¹⁸ and unlike those of other studies, such as Al-Naqqash et al., 2009¹⁶, Al-Sarraf et al., 2015¹⁹, and El-Fatemi and Chahbounil, 2012²⁰. In the present study, luminal A relapse was recorded in 69% of patients, while the reminder were non-luminal A; HER2-enriched, triple-negative and luminal B occurred in 14%, 14%, and 3% of patients, respectively. These results were inconsistent with the results of Fitzgibbons et al., 2000²¹ and Al-Sarraf et al., 2015¹⁹. Luminal A has the most favorable prognosis, with locoregional relapse rates of only 3–8% at 10 years²⁰. HER2-enriched groups exhibit the highest rates of local recurrence and regional relapse²¹.

Tumor size (T stage) was directly correlated with survival and metastasis in the present study. Size rank is among the strongest predictors of metastasis, disease-free survival (DFS), and OS. Although tumor size correlates strongly with the presence of axillary LNs, this is clearly an independent prognostic factor^5,21. Among those with documented negative nodes, tumor size remained a strong and independent predictor⁵. Many studies showed a 20 year DFS of 79% for those with tumors smaller than 2 cm, compared with 64% for those with tumors larger than 2 cm⁵. This study demonstrated T2 stage was the most common (53.9%), followed by T3, T1 and T4; regarding the T stage related to molecular subtype, T2/luminal A was most common (36.3%). These results were similar to those of Al-Rawaq et al., 2016¹⁴, Al-Khafaji et al., 2010¹⁵, and Al-Naqqash et al., 2009¹⁶, but different than those of Goldhirsch et al., 2013²² and Cheang et al., 2009¹⁸.

The status of LNs is an important prognostic factor related to survival and predictors of systemic micro-metastases²², disease recurrence, and poor prognosis²³. In the present study, the N1 frequency was 37.2% followed by N2, N0, and N4. The N1/luminal A frequency was 23.5%, which was recorded commonly, whereas the N3/luminal B frequency was the lowest (0.6%). These agree with the results of Al-Rawaq et al., 2016¹⁴ and Al-Khafaji et al., 2010¹⁵, while they disagree with those of Goldhirsch et al., 2013²² and Cheang et al., 2009¹⁸.

In the present study, the PFS, which was obtained using Kaplan Meier survival curves, estimated an association between receiving adjuvant radiotherapy and/or locoregional or recurrence rates and/or distant metastasis and/or the end point (death). The estimated resampling study findings in the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) in 2011, found that after BCS, radiotherapy halved the rate of recurrence and reduce the death rate by about a sixth²⁴, which was similar to that reported in the EBCTCG study in 2014, which found that radiotherapy beyond mastectomy and axillary dissection reduced both recurrence and mortality²⁵.

In the present study, non-relapse represented a large group (88.3%), whereas relapse was recorded in 11.7%, after a follow-up period from 6 to 12 months. Both proportional and absolute reductions in the recurrence rate are large in the first year, whereas the reduction in death becomes definite after the first few years⁵.

Conclusions

The fifth decade of life is the most common age of presentation for breast cancer in this Iraqi population, and the luminal A phenotype is the most common molecular subtypes. The commonest stage is T2 and N1, while the least common is T4 and N3. There was a strong correlation between age, BMI, and staging for molecular subtypes and hormonal status. Adjuvant radiotherapy treatment reduced locoregional recurrence, distant metastasis and death rates, and the period of waiting from last chemotherapy cycle to the date of radiotherapy represented a risk factor that affected the survival curve. Chest wall recurrence is most common site of disease progression.

Data availability