Decreased hormonal sensitivity after childbirth rather than the tumor size influences the prognosis of very young breast cancer patients

The frequency of breast cancers at less than 30 years of age is approximately 1% of
all breast cancers, and a younger age has been reported to have a worse prognosis
among premenopausal as well as all breast cancer patients (Maggard et al. 2003]; Cancello et al. 2010]). However, the recent recommendation of St. Gallen excluded a younger age as prognostic
factor (Glick et al. 1992]; Goldhirsch et al. 2001], 2009]; Colleoni et al. 2006]), and we previously reported that the prognosis of PABC is correlated with a younger
age (Makita et al. 2007]). In this study, a younger age was not found to be an independent prognostic factor,
although recent childbirth probably influenced the prognosis of the younger than 30
breast cancer patients by lowering their hormonal sensitivity. In addition, the prognosis
of PABC and very young breast cancer patients can be explained by considering the
interval from the last childbirth (Johansson et al. 2013]).

Factors such as Human Epidermal Growth Factor Receptor2 (HER2), Ki67 and the nuclear
grade were not investigated in this study because these parameters were not routinely
evaluated in the period of this case series. However, recurrence occurs earlier in
hormone receptor-negative cases (HER2 subtype and triple negative breast cancer) than
in cases of the luminal subtype (Metzger-Filho et al. 2013]), and the timing of recurrence is strongly influenced by hormonal sensitivity (Makita
et al. 2014]). We believe that the trend in the recurrence-free interval can be explained by hormonal
sensitivity alone, instead of based on the subtype. Even if additional data were available,
the results would not change regarding the chief influencing factor being hormone
sensitivity.

Although hormonal sensitivity is routinely evaluated based on the immunohistochemical
method, we intended to investigate the EIA data exclusively due to the assessment
to evaluate hormonal sensitivity quantitatively and objectively. The rates of a strongly
positive PgR status (?96 fmol/mg) differed based on YFLC. On the other hand, the analysis
of old case series and longer follow-up period showed that the RFS curve in the Younger
than 30 group gradually decreased, even after 10 years (Figure 3), whereas that in the Elder counterpart group reached a plateau. As for the relationship
between the results for PgR and the prognosis, the RFS rate in the cases in which
PgR EIA was not performed was as high as that noted in the cases with a strongly positive
PgR status. These cases likely belong to an earlier stage, as the lesions were difficult
to diagnose, except when performing an open biopsy, or were too small to obtain an
adequate sample for EIA. PgR has been reported to be an important prognostic factor
among cases of hormone sensitive breast cancer (Prat et al. 2013]), and the PgR status was found to be related to the prognosis, rather than the ER
status, in this study.

Whereas the number of years from the last birth was set at 8 years as the cutoff point
calculated according to the ROC in this study, the prognosis of the cases within 2 years
from the last childbirth has been reported to be worse (Mohle-Boetani et al. 1988]; Kroman et al. 1997]; Kroman and Mouridsen 2003]; Nagatsuma et al. 2013]). Despite the different cutoff points between previous and the present study, due
to the limited number of cases in this study, the trends displayed in these studies
were the same, and recent childbirth is thought to influence the prognosis of breast
cancer. This finding is related to a report showing that childbirth conveys a long-term
reduction in the incidence of breast cancer despite a transient, short-term increase
in the incidence of such cancer (Lambe et al. 1994]). Elevated levels of estrogens during pregnancy have been suggested to act as a promoter
of premalignant breast cells, thus explaining the transient increase in risk after
childbirth. It is probable that elevated levels of estrogens act as a stimulator of
malignant breast cells, which explains the transient increase in recurrent risk after
childbirth. Indeed, our data indicate that the prognostic influence of parity differs
between the patients less than 35 years of age and the patients 35–44 years of age.
Although the 10-year RFS rate of parous women was 49.0%, that of nulliparous women
was 62.9% (p = 0.0152) among the cases less than 35 years of age. On the other hand,
in the cases 35–44 years of age, the 10-year RFS rates of parous and nulliparous women
were 75.4 and 77.6%, respectively. In younger women, parity has an adverse effect
on the prognosis and this finding is related to a higher frequency of recent childbirth
in younger women. Because childbirth conveys a long-term reduction in the rate of
recurrence of breast cancer despite a transient, short-term increase in the frequency
of recurrence, the time of 8 years from the last childbirth is considered to be the
cutoff point for favorable effects rather than adverse effects.

The results showing that the case distribution of tumor size and number of lymph node
metastases did not differ between the groups demonstrated that the effects of confounding
factors between the two groups were successfully eliminated. Factors displaying differences
between the groups included the histological type, type of breast surgery and YFLC.
The rate of cases classified as solid-tubular carcinoma was higher in the Younger
than 30 group than in the Elder counterpart group, and the histological type was found
to be an independent prognostic factor as well as the number of lymph node metastases
in the multivariate analysis. Solid-tubular carcinoma and scirrhous carcinoma are
classified as poorly differentiated with a higher nuclear grade (Japanese Breast Cancer
Society 1989]) and have been reported to have a poor prognosis (Sakamoto 1989]). It is thought that young patients (35 years of age) with breast cancer are apt
to develop poorly differentiated lesions and display more aggressive features (Maggard
et al. 2003]; Kataoka et al. 2014]). On the other hand, the tumor size was not found to be an independent prognostic
factor in the current study. The worse prognosis of very young breast cancer patients
is thought to be related to tumor biology, including the histological features and
hormone sensitivity.

The number of the cases treated with breast conserving surgery was larger in the Younger
than 30 group than in the Elder counterpart group; however, the type of breast surgery
was not identified to be an independent prognostic factor in this study. Although
age has been reported to be an independent prognostic factor for ipsilateral breast
tumor recurrence (Arvold et al. 2011]), the number of cases of locoregional failure after surgery was almost the same in
the two groups in the current study. Therefore, the difference in the type of surgery
between the cases and controls did not necessarily influence the prognosis.

In the univariate analysis of the subgroup with 1–3 lymph node metastases, the rates
of 10-year RFS in the Younger than 30 and Elder counterpart groups were 59.7 and 85.6%,
respectively, and this difference was significant (p = 0.0329). As for the case distribution
in this subgroup (24 cases in the Younger than 30 group, 23 cases in the Elder counterpart
group), the rate of papillotubular carcinoma was lower and the number of cases in
which a hormone receptor analysis was not performed was larger in the Younger than
30 group. The reason for not performing a hormone receptor analysis was related to
the use of open biopsies before the diagnosis, mainly because the lesions were difficult
to diagnose correctly in the Younger than 30 group. Due to the lack of hormone receptor
status, these patients in the Younger than 30 group were treated with chemotherapy
only and were thus treated insufficiently, although we had no data about chemotherapy-induced
amenorrhea in these cases. It is probable that the decreased RFS in the younger women
was caused by the use of inadequate hormone therapy, as mentioned in other reports
(Colleoni et al. 2006]). Another probable cause is that most of these cases were treated before approval
was given for the use of luteinizing hormone releasing hormone agonist (LHRHA) as
adjuvant therapy.

As for family history and HBOC, there were no patients with BRCA mutations, and only one patient in the Younger than 30 group had a p53 mutation and
was diagnosed with Li-Fraumeni syndrome (Li and Fraumeni 1969]) among the two patients who received genetic tests. Five patients had more than one
case of breast cancer in their family in the Younger than 30 group; however, no cases
were observed in the Elder counterpart group. Over 15 years, the patients in the Younger
than 30 group had more cases of breast cancer or ovarian cancer in their families,
and it is probable that HBOC cases were included in this group. However, such cases
did not occupy the majority. Although the BRCA1 mutation is related to triple negative breast cancer (Lee et al. 2011]), a family history of breast cancer did not influence hormonal sensitivity in this
study, as three of five cases in the Younger than 30 group were PgR-positive.

A correlation between recent childbirth and the prognosis of malignant disease has
been reported and possible biological mechanisms of the adverse prognostic effect
include immunosuppression, the hormonal milieu in gestation and a tumor promoting
microenvironment post-partum (Moller et al. 2013]). However, decreased hormone sensitivity after childbirth is a probable chief cause
of adverse prognostic effects. Although collected data about the number of years from
recent childbirth from 207 cases was limited in this study, the breast cancer patients
who had given birth more recently showed an increased rate of PgR-negative tumors
in another report (Nagatsuma et al. 2013]). The correlation between recent childbirth and decreased hormone sensitivity was
demonstrated from the point of intensity evaluated using EIA in this study. The prognosis
of the very young women was the same as that for their elder counterparts, whose tumor
size was matched, and age was not an independent prognostic factor according to the
multivariate analysis. In conclusion, recent childbirth rather than the tumor size
probably influences the prognosis of breast cancer patients younger than 30 years
of age by lowering hormonal sensitivity.