In this retrospective cohort we evaluate the variable impact local control among a specific group of metastatic breast cancer undergoing surgery and post-operative RT. We found that the tumor biology, size, and are all significant for local control in addition to time from initial surgery.
Our local control rate is lower than previously studies that showed local control rate of 70–95% 4,7,11,12. That can be partially explained by a high percentage of patients receiving a lower dose of our trial compare to the others. In our study 46% received a BED (10) lower then 40 (i.e 25 Gy in 5 fraction) which recently been shown by Minnti et al to decrease local control 12.
We demonstrated correlation between dose and local control. In our analysis we used an α/β ratio of 4Gy which is more realistic in breast cancer tumors14. We notice that Dose above 70Gy(BED4) had HR of 0.51 (CI 0.16–0.91) even when adjusting to other variables.
Another explanation of the lower local rate results in our cohort is the timing from initial surgery until start of radiation. In a recent Meta-analysis of post-operative SRS showed a Lower local control when surgery-to-SRS delay longer than 3 weeks. The estimated 12-month control rates dropped from 87 to 61% if SRS was performed more than 3 weeks after resection 15. In our study the median day for starting radiation was 33. We found that starting radiation more than 30 days from surgery has a HR of 1.46 (1.13–2.78) for local failure.
In regards to other parameters. The average size of tumor in our cohort was similar to other studies16,17 and reflects the current change in practice to operate only on symptomatic large lesions, with the remainder undergoing definitive radiosurgery. Tumor larger than 3.5 cm had significantly worsen local failure with HR of 1.61 (CI 1.11–1.31).
The current guidelines recommend the inclusion of surgical tract with 1–5 mm margin13. In our cohort inclusion of surgical tract was seen in 64.7% of those who achieved local control and 55.5% at those who didn’t. However, this difference did not reach statistical significance.
Different studies had shown contradictory results on the impact of cystic lesions and response to local treatment. 18 Studies have suggested that the causes of cystic masses may include the breakdown of the blood–brain barrier or the higher risk of developing cystic BM in patients with poor histological grade,18,19. In addition, the complications seen in operations on cystic lesion and the less than Gross tumor resection achieved can have an impact on overall survival and local control respectively20. in our study cystic had much higher risk of local failure with HR of 1.55 (1.13–2.34).
Breast cancer biology
Different classical sub- types of breast cancer have different biology in regards of brain metastases prevalence, pathophysiology and response to treatment18. HER2-positive breast cancer has the inherent tendency of metastasis to the brain but because of variable systemic treatment options with good brain response and even longer survival among all breast cancer population with brain metastases20.
Surprisingly, in our cohort patients the prevalence of HER-2 sub type was higher among those who achieved local control. Having HER-2 disease decrease the odds for local failure by 37% even when adjusting to different dose. This can be explained by the fact that most patients in our cohort had visceral metastatic disease and received systemic therapy after the course of radiation. HER-2 targeted therapy like transtuzumab, transtuzumab-emtansine, fam-transtuzumab-deruxtecan, lapatinib with capecitabine and tucatinib have all high response rate in the CNS21 and can help reduced the risk of recurrence by effectively treating microscopic disease. This advantage is lacking in other sub-type populations.
Using the cox regression analysis, we built a nomogram for local failure. Figure 1.
Toxicity
We found 8 cases of reported radiation necrosis on MRI. All of whom were asymptomatic. Of these patients, four received 65.31Gy, two received 87.75Gy and two received 72Gy (all using BED4). 38% reported Grade 2 fatigue and 11% with Grade 2 headache.