Breast Cancer Res Treat. 2015 Jul;152(2):377-87.

Outcome after neoadjuvant chemotherapy in young breast cancer patients: a pooled analysis of individual patient data from eight prospectively randomized controlled trials.

 

Loibl S1,2, Jackisch C2, Lederer B1, Untch M3, Paepke S4, Kümmel S5, Schneeweiss A6, Huober J7, Hilfrich J8, Hanusch C9, Gerber B10, Eidtmann H11, Denkert C12, Costa SD13, Blohmer JU14, Nekljudova V1, Mehta K1, von Minckwitz G1.

1German Breast Group, c/o GBG Forschungs GmbH, Martin-Behaim-Straße 12, 63263 Neu-Isenburg, Germany; 2Sana-Klinikum, Offenbach, Germany; 3Helios-Klinikum, Berlin-Buch, Germany; 4Technische Universitäts-Frauenklinik, Munich, Germany; 5Brustzentrum Kliniken Essen-Mitte, Essen, Germany; 6Universitäts-Frauenklinik, Heidelberg, Germany; 7Universitäts-Frauenklinik, Ulm, Germany; 8Eilenriede Klinik, Brustzentrum, Hannover, Germany; 9Klinikum zum Roten Kreuz, Munich, Germany; 10Universitäts-Frauenklinik, Rostock, Germany; 11Universitäts Frauenklinik, Kiel, Germany; 12Institute of Pathology, Charité University Hospital, Berlin, Germany; 13Universitäts-Frauenklinik, Magdeburg, Germany; 14Brustzentrum, Charité, Berlin, Germany.

 

Abstract

Young women with breast cancer (BC) have a worse survival partly due to more aggressive tumor characteristics; however, their response to chemotherapy seems better. We investigated to what extent the prognostic factor pathological complete remission (pCR) after neoadjuvant chemotherapy is applicable to young women. 8949 patients with primary BC and follow-up from eight German neoadjuvant trials were included. A subgroup of 1453 patients <40 years was compared with women aged 40–49 and ≥50 years regarding pCR (ypT0 ypN0, no invasive and no non-invasive residuals tumor in the breast and nodes), as well as disease free survival (DFS), local recurrence free survival (LRFS), distant disease free survival (DDFS), and overall survival (OS) overall, according to pCR status and subtypes defined by hormone-receptor (HR) status and HER2. pCR was strongly associated with age without a clear age cut-off. The pCR rate was significantly higher in the young compared with other age groups (20.9 vs. 17.7 vs. 13.7%; p<0.001). This difference was confined to triple-negative breast cancer (TNBC, hormone receptor negative and HER2 negative BC) and HR+/HER2-. DFS, DDFS, LRFS, and OS were significantly worse for young women. Age was independently prognostic for survival in HR+/HER2-, with women <40 years without pCR having a worse DFS compared to their counterparts with pCR. Young women are more likely to achieve pCR after neoadjuvant chemotherapy, especially in HR+/HER2- and TNBC. Age is not an important prognostic factor in TNBC and HR-/HER2+ but is in HR+/HER2-. Young women with a luminal-like BC (HR+/HER2-) seem to benefit more from neoadjuvant chemotherapy than older women, which needs to be taken into account.

PMID: 26109347

 

Supplement:

Approximately 7% of women affected by breast cancer are younger than 40 years.1 Even if breast cancer in young women can be considered a rare disease compared to the incidence in older women, it needs special attention. This may be because young age has been shown to be associated with worse outcome mainly due to more aggressive tumor characteristics.2 Although they achieve a higher rate of pathological complete response after antracycline/taxane-based neoadjuvant chemotherapy3, young women remain at higher risk of relapse; strangely, if we consider that pCR is usually regarded as a favorable prognostic factor.4,5 Therefore, a doubt has risen: can pCR still be considered a favorable prognostic factor, even in young women? If so, is the statement valid in all breast cancer subtypes? And if our young patients fail to obtain a pCR, is that associated with a worse outcome compared to older women? In order to answer all these burning questions we collected individual data of 8949 patents enrolled in 8 different neoadjuvant trials from 1998 to 2010. Of those 1453 were aged <40 years. Patient characteristics (age, body mass index), tumor characteristics (tumor and nodal stage, histological type, tumor grade, hormone receptor (HR) and HER2 status) and follow-up data were all required for the analysis. Women younger than 40 years tended to have smaller tumors, less lymph node involvement, more ductal invasive, grade 3 and hormone receptor negative tumors. Moreover, one third of them presented with a triple negative breast cancer (TNBC) subtype.

When the whole patient cohort was analyzed an important result emerged: the younger the patients were the higher was the pCR rate. The continuous correlation between age and pCR has not been previously shown and can be elegantly represented with a STEPP-like diagram (Figure 1).

 

Fig1

Figure 1. Correlation between age and pCR. STEPP-like analysis of age and pCR (ypT0 ypN0)

 

Young age seems to play a different role regarding pCR according to the biological subtype. In particular, age is an independent predictive factor for pCR in TNBC and HR+/HER2- breast cancer patients, with TNBC patients having a 4-5 fold higher chance to achieving a pCR (Figure 2). Despite a better chemotherapy response, women younger than 40 years had a significantly worse local-recurrence free (LRFS), distant-disease free (DDFS) and disease free survival (DFS) compared to older age groups especially if not achieving a pCR and in particular in the HR+/HER2- group. Interestingly, it seems that the benefit of achieving a pCR by applying neoadjuvant chemotherapy in the HR+/HER2- cohort translates into a survival benefit which could not be demonstrated in the other age groups within the same cohort. We have previously shown that pCR is not an important prognostic factor for HR+/HER2- tumors, especially in the luminal-A like subgroup (HR+/HER2-/G1-G2).4,5 We can only postulate that age seems the only important risk factor in this cohort. In fact the low number of events and the generally good prognosis of this group do not allow us to draw any conclusions. In line with the recent HERA trial results we also showed that age did not play any role in HER2+ patients, HER2 itself being the dominating prognostic factor in this group.6 One can also argue that anti-HER2 treatment is so effective that the age effect is abolished.

Taken together, our results underline the fact that most likely age remains a prognostic and/or predictive factor when all other factors, e.g. HER2, do not play a role.

 

Fig2

Figure 2. Forest Plot for multivariable logistic regression presenting the odds of achieving a pCR by subtype for the various age groups.

 

We still need to clarify why young women have a worse outcome despite the high pCR rate they can achieve. Probably they have tumors that are biologically different compared to those of older women.7 Moreover, there are data demonstrating that in very young women (<35 years) poor survival outcome maybe due to tamoxifen resistance. Despite the ABCSG12 study and the SOFT trial recently demonstrating the efficacy of endocrine therapy in young women too, the better outcome seen in the adjuvant SOFT trial was obtained owing to the association of aromatase inhibitors or tamoxifen with ovarian function suppression.8,9,10 Since patients in our analysis were treated in the neoadjuvant setting, they did not receive ovarian function suppression. Therefore, we can not exclude a better outcome result for our young patients, had they been treated with a combined endocrine treatment.

Summarizing, why is our study important? We have shown for the first time the existence of a continuous correlation between age and pCR rate. Moreover, our analysis clearly shows that pCR is a reliable prognostic factor in young women. Achieving a pCR is of major importance especially in patients with HR+/HER2- tumors given an improvement of DFS and DDFS not seen in their older counterparts (Figure 3). Therefore, the use of neoadjuvant chemotherapy in young patients with luminal like tumors should be carefully considered.

 

FIG3

Figure 3. Disease Free Survival in patients with HR+/HER2- tumors by pCR.

 

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Acknowledgement: We would like to thank all patients, investigators, and study personnel who supported the trials and the German Breast Group for support.

 

 

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