ESMO @ ECC 2013: Premenopausal High-Risk Breast Cancer Patients with Luminal A Tumours Benefit from Postmastectomy Radiation

Findings from two small independent randomised trials suggest adjuvant radiotherapy should not be omitted in young patients with high-risk tumours.

The PAM50 assay was used to identify a subgroup of patients with node positive breast cancer who derived increased long term benefit from chemotherapy plus radiation over chemotherapy alone following mastectomy; premenopausal women with luminal A tumours showed significantly decreased local disease recurrence from the addition of radiation to chemotherapy following surgery in an analysis of long term follow-up data from two small independent studies.

Findings were presented on 28 September during the Breast Cancer/Advanced Disease segment of the Proffered Papers Session (Abstract E17-1573) at the 17th ECCO – 38th ESMO – 32nd ESTRO European Cancer Congress in Amsterdam, The Netherlands. The Congress was held from the 27 September through the 1 October, 2013 and was part of a series of European Cancer Congresses that are organised in joint partnership with ESSO, EACR, EONS and SIOPE to offer multidisciplinary and multi-professional educational opportunities in oncology.

ESMO Comments bubble

The study presented by Dr. Laurberg and colleagues investigated the benefit from post-mastectomy radiotherapy (PMRT) based on biological subtypes defined by PAM50 in premenopausal women with node positive primary breast cancer, who participated in two studies investigating the effect of PMRT in addition to CMF back in the 90s.
A total of 128 FFPE samples and 87 fresh frozen samples were available for testing. The investigators observed an additional benefit for improved local-recurrence free survival (LRFS) by PMRT for women with Luminal A tumours in both cohorts but not in any other subtype, although in the British Columbia study PMRT also significantly increased LRFS in triple-negative breast cancer from 25% to 92%.
While this is a very interesting study using modern gene expression techniques, based on two large, prospectively randomised phase III trials with a 20 year follow-up, this study has a number of pitfalls which needs to be addressed. First of all, the main criticism remains that women only received CMF chemotherapy, which is today no longer the standard for node-positive breast cancer. Other points are the small number of women with tumour material for PAM50 assessment. In addition to that the number of events on which the results are based on within the subgroups become really small (1/6). This makes is really difficult to draw a conclusion. In addition such a small number of patients will never be able to show any effect on overall survival.
Having said that, I still believe this is an interesting study to build upon and try to identify young women who benefit from PMRT. Actual recommendations support PMRT in very young women with additional risk factors. However, we know in young women the risk profile is probably different from others and they might benefit from additional therapy even if they have a Luminal A tumour. But this warrants further investigations.

Sibylle Loibl*

*Sibylle Loibl, ESMO spokeperson who was not involved in the study

A substantial risk for late loco-regional relapses in patients with luminal A breast cancers

Luminal A tumours are a double edged sword: While they are associated with a good prognosis they also carry a substantial risk for late loco-regional relapses. Tinne Laurberg of the Department of Experimental Clinical Oncology, Aarhus University Hospital, Aarhus, Denmark headed a team in conducting an analysis of data after 20 years of follow-up from two independent, similarly designed randomised trials to determine whether intrinsic subtypes identified by PAM50 classification could be predictive of long term loco-regional relapse after adjuvant radiation therapy was administered to preenopausal women following mastectomy.

The analysis was done only on data where accompanying biological samples were available from participants in either of the postmastectomy randomised adjuvant radiation trials conducted by the British Columbia Cancer Agency [Ragaz et al.NEJM 1997 Oct 2; 337(14):956-62]and the Danish Breast Cancer Cooperative Group (DBCG 82b) [Overgaardet al. NEJM 1997 Oct 2; 337:949-955].

The team performed gene expression profiles using the Nanostring Counter®  on 128 formalin fixed paraffin embedded (FFPE) tissues that were available from the British Columbia (BC) trial and the Human Genome Survey Microarray version 2.0 (Applied Biosystem) for the 87 fresh frozen (FF) samples from the Danish Breast Cancer Cooperative Group (DBCCG). Each tumour was classified into Luminal A (LumA), Luminal B (LumB), Her2-enriched (Her2-E), Basal-like (BLBC) and Normal-like subtypes according to the PAM50 assay.

The differences per subtype in local-regional relapse free survival (LRFS) and overall survival (OS) were determined by Kaplan-Meier analysis and the log-rank test.

All patients had node positive breast cancer. Following mastectomy patients in both trials received adjuvant cyclophosphamide, methotrexate, fluorouracil (CMF) chemotherapy and were randomised to receive either radiation therapy (RT) that entailed irradiation of the chest wall and regional lymph nodes or no RT. The BC trial had a second randomisation; patients with estrogen receptor positive tumour were randomised to receive oophorectomy and data from 42 of these patients were included in this correlative study.

Radiation should not be omitted in young patients with high-risk tumours

The 20 year LRFSrate evaluated according to subtypes showed that women with LumA tumours who received postmastectomy radiotherapy had a significantly better LRFS; of 41 women with LumA tumours participating in the BC trial, 94% of women who received adjuvant radiotherapy had no local recurrence compared to 66% of women who received chemotherapy only (p = 0.05). Similar results were seen in the 20 women with LumA tumours in the DBCG trial where 92% of women in the radiotherapy group had no local recurrence compared to just 25% of women who received only chemotherapy (p = 0.01).

No statistically significant differences were observed for LRFS for LumB and Her2-E subtypes in either trial. However, in woman with BLBC subtype, 92% of women receiving radiotherapy compared to 23% in the chemotherapy only group achieved LRFS in the BC trial (p = 0.004); the rates for LRFS for BLBC were similar between treatment groups in the DBCG trial.

This analysis found no differences in OS between the tumour subgroups in either trial. However, findings from the DBCG trial showed OS was increased at a 10 year follow-up in the entire population with radiotherapy plus chemotherapy over chemotherapy alone: 54% of adjuvant radiotherapy patients versus 45% of chemotherapy alone were alive at 10 years (p < 0.001).

These results suggest that PAM50 Luminal A classification identifies patients with slow growing tumours who may obtain the greatest benefit from regional radiotherapy following mastectomy. The clinical implication is that radiation should not be omitted in young premenopausal patients with high-risk tumours.

The investigators reported no conflicts of interest.