In this retrospective cohort, we evaluate the variable impact of local control among a specific group of metastatic breast cancer undergoing surgery and postoperative RT. We found that the tumor biology size is significant for local control in addition to time from the initial surgery.
Our local control rate is lower than previous studies that showed a 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 compared to the others. In our study, 46% received a BED (10) lower than 40 (i.e., 25 Gy in 5 fractions), which has recently been shown by Minnti et al. to decrease local control 12.
We demonstrated a 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 a Dose above 70Gy(BED4) had an 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 the start of radiation. A recent meta-analysis of postoperative SRS showed a lower local control when surgery-to-SRS delay is longer than three weeks. The estimated 12-month control rates dropped from 87 to 61% if SRS was performed more than three 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 an HR of 1.46 (1.13-2.78) for local failure.
The average size of the tumor in our cohort was similar to other studies16,17. It reflected the current change in practice to operate only on symptomatic large lesions, with the remainder undergoing definitive radiosurgery. Tumors larger than 3.5 cm had significantly worsened local failure with an HR of 1.61 (CI 1.11-1.31).
The current guidelines recommend the inclusion of a surgical tract with a 1-5 mm margin13. In our cohort, the inclusion of surgical tract was seen in 64.7% of those who achieved local control and 55.5% of those who did not. However, this difference did not reach statistical significance.
Different studies have 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 the cystic lesions and the less than Gross tumor resection achieved can have an impact on overall survival and local control, respectively20. In our study, cystic had a much higher risk of local failure with HR of 1.55 (1.13-2.34).
Toxicity
We found 8 cases of reported radiation necrosis on MRI. Two of whom were asymptomatic. The two symptomatic patients were treated successfully with dexamethasone. In the entire cohort, 38% reported Grade 2 fatigue, and 11% with Grade 2 headache.
Breast cancer biology
Different classical sub-types of breast cancer have different biology in regards to brain metastase 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 more prolonged survival among all breast cancer populations with brain metastases20.
Surprisingly, the prevalence of the HER-2 subtype in our cohort patients was higher among those who achieved local control. Having HER-2 disease decreases the odds of local failure (OR=0.2). The population of patients with HER-2 disease was not different in any of the other variables from the population of HER-2 negative disease (table 5)
The difference in local control can be explained by the fact that most patients in our cohort had visceral metastatic disease at presentation and received systemic therapy after the course of radiation. HER-2 targeted therapy like trastuzumab, trastuzumab-emtansine, fam-transtuzumab-deruxtecan, lapatinib with capecitabine and tucatinib have all high response rates in the CNS21,22. The TUDEXO-1 trial recently showed an 83% intracranial response23. Moreover, it can help reduce the risk of recurrence by effectively treating microscopic disease. This advantage is lacking in other sub-type populations.
Our study has some limitations, including the retrospective nature of the data and the fact that it is a single-institution analysis.
On the other hand, the advantage of our study is the relatively large homogenous cohort of only breast cancer patients with single brain metastases who had a resection. Most of the Current literature on postoperative radiotherapy analyzed all subtypes of cancer in the same manner without consideration of the different biology of each tumor type.