Axillary LN volumes (average = 4.07 cm3) of the I-SPY 1 TRIAL breast cancer patients were significantly larger than our normal axillary LN volumes (average = 0.646 cm3). There are no similar studies with which to quantitatively compare to our study but our findings are in agreement with the notion that axillary LNs < 1.5 cm diameter are generally considered normal-appearing.19 A 1.5 cm diameter LN translates to a volume of 1.77 cm3 assuming a sphere which is comparable to our cutoff of 1.98 cm3 for the large axillary LN group. Nodal and full PCR did not depend on pre-NAC axillary LN volume, suggesting that NAC is equally effective whether the patients started out with large or small nodes in this cohort. Thus, pre-NAC axillary LN volume alone may not be predictive of full or nodal PCR.
The patients with HR+/HER2– subtype cancers had smaller maximum axillary LN volumes than that of the patients with HER + and TN subtype cancers, consistent with the notion that HR+/HER2– subtype cancers are comparatively less aggressive. On the other hand, HER2 + subtype breast cancers are known to be more aggressive. As chemotherapy is generally more effective with proliferative cancers, the HER2 + subtype breast cancer patients with large maximum LN volumes who achieved great response to chemotherapy may have had the longest RFS since not only did they have a cancer subtype susceptible to chemotherapy, but showed evidence of significant response by achieving PCR in the presence of large axillary LNs.20
When patients were subgrouped into patients with large axillary LN and patients without pre-chemotherapy, there was no significant difference in RFS. This is in contrast to head and neck, lung, and esophageal cancers, where large LN volume negatively impact survival.12, 13, 21 Interestingly, when substratified by pathologic response outcomes, the large axillary LN group with full or nodal PCR showed better RFS. This was not the case for the small axillary LN group. This may be the result of treatment effect heterogeneity as the large node group had more HER2 + subtype cancers. Since there is a higher proportion of HER2 + cancers in black or African Americans and HER2 + subtype cancers are comparatively more aggressive, it is understandable that black or African Americans had larger axillary LNs.18, 20 In short, pre-NAC axillary LN volume did not inform RFS in any sub-stratification but appeared to inform RFS when it is combined with PCR status. This innovative observation could mean that If the NAC regimen can successfully treat a large node to a complete remission, this probably means the treatment is very effective, which may lead to a better RFS. This finding could have practical clinical utility.
Survival was similar across all 3 molecular subtypes despite HR+/HER2 − patients having the worst full PCR, consistent with literature.3 This suggests that even though HR+/HER2 − had markedly poorer PCR rates, the post-NAC treatment was equally effective among the 3 molecular subtypes. Interestingly, there was significant difference in Kaplan − Meier estimates among the 3 molecular subtypes for the small but not the large axillary LN group. HER2 + subtype patients fared significantly worse when compared to the HR+/HER2 − subtype patients but not the TN subtype patients. This was unexpected since both HR+/HER2 − and TN subtype patients had around 70% survival at the 10-year mark. This finding suggests that there is a markedly different pattern of survival between HR+/HER2 − and TN subtype patients with TN subtype patients having recurrence or expiring more commonly within the first 5 years. There are likely unaccounted factors of TN cancers that make patients susceptible to recurrence within the first 5 years after NAC, such as Ki-67 status. This observation needs to be interpreted with caution as there is potential of bias due to small sample sizes.
There are several limitations in this study. A limitation is the small sample sizes after sub-stratification into axillary LN volumes, PCR status, and molecular subtypes. These findings need to be replicated on a large sample sizes to be generalizable. Another limitation was that there was no pathological confirmation of the diseased nodes. It is challenging to identify the same nodes on MRI that was biopsied. Nonetheless, the largest axillary LNs in this study were confirmed to be the most suspicious of malignancy due to morphological features, such as loss of fatty hilum, increased size, and/or thickening of cortex by our expert radiologists. Additionally, although radiologists tend to measure long and short diameter, we did not make this measurement because volumetric measurements were more reliable especially for small size objects. Future studies to improving MRI spatial resolution and contrast of axillary LNs and applying texture analysis and artificial intelligence to the axillary LNs, among others, could yield additional clinically useful information. Patients with different molecular biomarker subtypes usually received different adjuvant treatments, e.g. hormonal therapy in HR + patients, and additional HER2 targeting therapy for maintenance in HER2 + patients. These could affect the RFS. However, the sample size was insufficient to further divide based on post NAC treatment.