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Paolo Lissoni1*, Giuseppe Di Fede1,
Antonio Battista2, Giusy Messina1, Remo
Egardi1, Fernando Brivio3, Franco Rovelli1,
Massimo Colciago4, Giuseppe Brera5
Summary
The recent advances in the psychoneuroendocrinology have
suggested the possibility to modulate tumor hormone dependency
through a neuroendocrine approach. In particular, it has been
proven that the pineal neurohormone melatonin (MLT) may
stimulate estrogen receptor (ER) expression in breast cancer
cells and inhibit the aromatase activity. On this basis, a study
was planned to evacuate the efficacy of a concomitant treatment
with the aromatase inhibitor anastrozole plus MLT in metastatic
breast cancer. The study included 14 metastatic breast cancer
women of poor clinical conditions with ER positive or unknown.
Both anastrozole and MLT were given orally at a dose of 1 mg at
noon and of 20 mg in the evening, respectively. The clinical
response consisted of complete response in 2 and partial
response in 6 patients. Then, an objective tumor regression was
achieved in 8/14 (57%) patients, with a median duration of 26
months. No neoplastic cachexia occurred on treatment. This
preliminary study shows that a neuroendocrine strategy with
anastrozole plus the pineal hormone MLT may represent a new
effective and well tolerated regimen in the treatment of
metastatic breast cancer women, including those with poor
clinical status, with therapeutic results apparently superior to
those reported in the literature with the only aromatase
inhibitor. Then, these results would justify further randomized
studies of aromatase inhibitors with or without a concomitant
administration of MLT, in an attempt to establish whether the
pineal hormone may enhance the efficacy of the aromatase
inibibitors in the treatment of human advanced breast cancer.
I. Introduction
Recent experimental studies have demonstrated that the hormone
dependency is at least in part under a psychoneuroendocrine
regulation (Cos et al, 2008;Grant et al,
2009). In particular, it has been shown that the pineal
hormone melatonin (MLT), whose anticancer properties have been
well demonstrated (Bartsch et al, 1981;
Maestroni, 1993; Reiter et al, 2002), may in vitro
stimulate estrogen receptor (ER) expression on breast cancer
cell lines (Molis et al, 1995).
Therefore, the hormone dependency of breast cancer cells would
not depend only on intrinsic characteristics of cancer cells
themselves, but also on host neuroendocrine regulation of tumor
cell proliferation and differentiation (Bartsch
et al, 2000). Moreover, cancer progression has been
proven to be associated with pineal alterations, consisting of a
progressive decline in MLT nocturnal production. (Maestroni,
1993). Therefore the advanced cancer would require a
substitutive endocrine therapy with MLT (Bartsch
et al, 1981; Maestroni, 1993). Previous preliminary
clinical studies had already suggested that the concomitant
administration of the pineal hormone MLT may apparently increase
the efficacy of tamoxifen therapy in the treatment of metastatic
breast cancer (Lissoni et al, 1995).
Moreover, experimental studies have shown that the activity of
aromatase enzyme, which is responsible for the peripheral
production of estrogens from testosterone (Bagatell
et al, 1994), is under a light/dark circadian rhythm (Bhatnagar
et al, 1992). Because of the fundamental role of the
pineal hormone MLT in the regulation of the daily photoperiod (Bartsch
et al, 1981), it is possible to hypothesize that MLT may
be involved in the control of the aromatase activity. In fact,
recent studies have demonstrated an inhibitory action of MLT on
the aromatase activity (Cos et al, 2005).
This finding could reserve a prosiming application in the
treatment of both early and advanced breast cancer. This
statement is justified by the fact that the aromatase inhibitors
represent a new class of agents in the endocrine treatment of
breast cancer Plourde et al, 1994), with a potential efficacy
superior to that achieved by the previous hormonal therapies
with anti-estrogens, such as tamoxifene, even though tumor
response rate obtained by the aromatase inhibitors are generally
not greater than 40%. On this basis, a phase II study was
planned in an attempt to evaluate the efficacy of a
neuroendocrinotherapeutic regimen consisting of a concomitant
administration of the aromatase inhibitor anastrozole and the
pineal hormone MLT in metastatic breast cancer women with poor
clinical conditions.
II. Materials and methods
The study included 14 consecutive metastatic breast cancer women
(median age: 72 years, range 51-82), who were followed at
Biological Medicine Institute in Milan, or at Health Local Unit
2 of Avellino, from Feb. 2002 to Sept. 2003. Eligibility
criteria were, as follows: histologically proven metastatic
breast cancer, measurable lesions, ER positive or unknown, no
ability to tolerate chemotherapy because of age, low performance
status (PS), important clinical illnesses other than cancer
and/or heavy chemotherapeutic pre-treatments, no previous
endocrine therapies for the metastatic disease, no double tumor
and life expectancy less than 1 year. Previous heavy
chemotherapeutic treatment consisting of at least 3
chemotherapeutic lines was made in 11/14 (79 %) patients.
Dominant metastasis sites were, as follows: soft tissues:1; bone:1;
lung:7 (neoplastic lymphangitis:2); liver:1; lung + liver:1;
bone marrow:3. Time-span since first diagnosis of the primary
tumor was 44 months (31-66 months). All patients had an
acceptable social conditions. The minimum and median follow-up
periods were 60 months and 72 months respectively. In all
patients, in the case of disease progression, at least to other
endocrine therapeutic lines with other aromatase-inhibitors were
planned. The experimental protocol, wich was approved by the
Health Direction of Biological Medicine Institute of Milan, was
explained to each patient and informed consent was obtained. The
treatment consisted of anastrozole at a dose of 1 mg/day orally
at noon, plus MLT at 20 mg/day orally in the evening, generally
half-hour before sleeping, to correct cancer progression-related
decline in MLT night secretion (10). Patients were considered to
be evaluable when they were treated for at least 3 consecutive
months. The clinical response was evaluated according to WHO
criteria. Complete response (CR) was the complete disappearance
of all neoplastic lesions for at least 1 month. Partial response
(PR) was a reduction greater than 50 % of the sum of all
neoplastic lesions, for at least 1 month. Stable disesase (SD)
was no increase or decrease greater tha 25 % of tumor volume.
Progressive Disease (PD) was an increase in tumor volume greater
than 25 % or the appearance of new neoplastic lesions. PS was
assessed according to Karnofsky’s score, consisting of the
evaluation of the quality of life in relation to patient
activity and bed-rest period. ER was positive in 10 and unknown
in the remaining 4 patients. The median PS was 80% (range
70-100). Data were statistically evaluated by the chi-square
test and the Student’s t test, as appropriate.
III. Results
All patients were fully evaluable for the clinical response. The
clinical characteristics of patients and their individual
clinical response to the treatment are reported in Table 1.
As reported, a complete response (CR) was achieved in 2/14 (14%)
(soft tissues:1; lung lymphangitis:1). A partial response (PR)
was obtained in other 6/14 (43%) (bone:1; lung:3; liver:1; bone
marrow:1). Then, an objective tumor response (CR + PR) was
reached in 8/14 (57%) patients. The median duration of response
was 26 months (range 9-42 months). A stable disease (SD) was
seen in other 4/14 (29%), with a median duration of 25 months (range
10-27). Therefore, a disease-control (DC:CR + PR + SD) was
achieved in 12/14 (86%) patients, whereas the remaining 2/14
(14%) patients had a progressive disease (PD). No significant
difference in tumor response rate was observed between patients
with positive or unknown ER ( 6/10(60%) vs 2/4(50%) ). An
overall survival at 1 year and at 3 year was achieved in 11/14
(79 %) and in 5/14 (36 %) patients, respectively. Moreover, 3/14
(21%) patients were still alive at 5 years. The treatment was
well tolerated in all patients.
Moreover, most patients experienced a relief of asthenia
under the treatment and in no patient the neoplastic cachexia
occurred. Finally, an evident increase in PS mean values was
achieved under treatment, even though it did not reach the
statistical significance (86 ±5 vs 93 ± 4, mean ± SE).
IV. Discussion
The results of this preliminary phase II study, by showing a
percentage of 1-year survival greater than 70% in patients with
live expectancy less than 1 year, would suggest that a
neuroendocrine regimen consisting of the aromatase inhibitor
anastrozole plus the pineal neurohormone MLT may represent a new
effective therapeutic strategy in the treatment of metastatic
breast cancer women, also in patients with poor clinical
conditions, who would not be able to tolerate the most
aggressive therapies. The concomitant administration of the
pineal hormone would seem to enhance the efficacy of the
aromatase inhibitor in terms of objective tumor regressions with
respect to the results commonly reported in the literature with
the only aromatase inhibitor (Plourde et
al, 1994), which are generally lower than 40%.
The time to progression would seem to be apparently increased
by the concomitant treatment with MLT.This finding is not
surprising, since MLT could enhance the therapeutic anticancer
acitivity of the aromatase inhibitors by either exerting direct
antiproliferative antitumor effects (Bartsch
et al, 1981; Maestroni, 1993; Reiter et al, 2002), or
further inhibiting the aromatase activity by acting on gene and
oncogene expression (Molis et al,1995; Cos
et al, 2005). In addiction, MLT appeared to stimulate ER
expression of breast cancer lines, by transforming ER negative
into ER positive breast cancer, as observed in experimental
conditions (Danforth et al, 1983).
Since the prognosis of ER positive breast cancers is clearly
better than that of ER negative ones, MLT could per se improve
the clinical couse of mammary tumors. Finally, because of its
interesting therapeutic efficacy as a supportive care (Reiter
et al, 2002), MLT would be responsible for the evident
improvement in the relief of asthenia and in preventing the
occurrence of the neoplastic cachexia. On the other hand,
because of the inhibitory effect of MLT (Grant
et al, 2009; Reiter et al, 2002) on cancer cell
proliferation, the anticancer activity of this polyendocrine
regimen would be due not only to an indirect effect, depending
on a diminished estrogen production following aromatase enzyme
inhibition, but also on a direct inhibition of cancer cell
growth, due to MLT itself. Therefore, the results of this
preliminary study may justify further clinical randomized
investigations with the only aromatase inhibitor versus the
concomitant treatment with MLT, in an attempt to confirm the
ability of the pineal hormone to enhance the antitumor
properties of the aromatase inhibitors in the treatment of
metastatic breast cancer women with poor clinical conditions.
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