Based on these results it can be envisioned that the majority of endocrine-responsive
post-menopausal breast cancer patients will be treated with an AI as adjuvant therapy
(front-line, switching or extending) and/or as first-line management of metastatic breast
cancer.
In presence of ER hypersensitivity even a small amount of ER may be sufficient for sustained
growth signalling. On the other hand, ER disruption operated by fulvestrant is not complete,
particularly in the initial phase of treatment. From phase III trials, indeed, The
invertigators know that with the standard 250mg monthly dose the steady state of circulating
drug is reached only after 5-6 injections. This may play a role since, as long as ER
downregulation is concerned, a clear dose-response relationship has been reported. In such a
situation, fulvestrant efficacy may be partial, particularly because the concomitant AI
discharge yields a restoration of physiologic postmenopausal levels of circulating
oestrogens. New dosing schedule are currently under investigation both to accelerate the
achievement of the steady state (loading dose) and to achieve higher circulating drug levels
(high dose) (86).
In this trial the investigators will be using the so-called 'loading dose'.
Further potential strategies to improve fulvestrant efficacy in this setting are:
A) avoid the restoration of circulating oestrogens; B) interfere with molecular mechanisms
that produce ER hypersensitivity by targeting the EGFR/ERBB2/ERB3 system.
A) avoid the restoration of circulating oestrogens: this should be achieved by holding the AI
treatment. Because some cases of progression upon AIs may be related to an inefficient
inhibition of the aromatase it is a logical step to test whether changing AI class (from type
I, steroidal, to type II, non steroidal, and vice-versa) (87), may improve fulvestrant
efficay. In this view, pts in this trial will be randomized to receive fulvestrant (loading
dose) with or without the alternate class AI treatment. Circulating oestrogens levels will be
tracked to verify inhibition of aromatase for pts assigned to concurrent AI treatment.
B) Interfere with growth factors-mediated ER hypersensitivity: although fulvestrant is able
to overcome the ER hypersensitivity of LTED (88) and produce a growth arrest, this activity
may not be complete because of incomplete ER disruption, but also because of a direct
stimulation of growth by the hyperactivated EGFR/ERBB2/ERB3 system. Laboratory evidence
support this hypothesis. Indeed, breast cancer cell lines exposed to long-term treatment with
fulvestrant became insensitive to the drug and restore growth (89). This growth does not
appear, however, related to the development of direct resistance to the drug, since ER
mediated signalling continue to be efficiently suppressed in these cells; rather it may be
driven by the use of alternative growth-stimulating pathway, including the EGFR system.
Indeed, it can be abrogated by the EGFR-tyrosine Kinase inhibitor Gefitinib (IRESSA™) and by
an MAPK-inhibitor (90). Lapatinib (GW572016) is an orally active small molecule that
reversibly inhibits ErbB1 and ErbB2 tyrosine kinases, which in turn blocks phosphorylation
and activation of Erk1/2 (p-Erk1/2) and Akt (p-Akt) in ErbB1- and/ or ErbB2-expressing tumor
cell lines and xenografts (91-94). Lapatinib elicits cytostatic or cytotoxic antitumor
effects depending on the cell type (95;96). Because ErbB2-containing heterodimers exert
potent mitogenic signals, simultaneously interrupting both ErbB1 and ErbB2 signaling is an
appealing therapeutic approach. Moreover, ErbB3 signaling is also involved in lapatinib
action. Indeed ErbB3 is kinase-dead and relies on ErbB2 for transactivation: ErbB2-ErbB3
heterodimers are potent activators of the PI3K-Akt survival pathway (97;98), which can, in
turn, inhibited by lapatinib.
Based on its molecular mechanism of action, on its fair toxicity profile and on its
promising, although preliminary, activity data, Lapatinib appears an ideal candidate to
combine with Fulvestrant in the attempt to improve its efficacy in patients progressing on
AIs.
Inclusion Criteria:
1. Provision of written informed consent
2. Histological/cytological confirmation of breast cancer
3. Documented positive hormone receptor status (ER+ve and/or PgR+ve) of primary or
metastaic tumor issue, according to the local laboratory parameters
4. Postmenopausal women
5. Confirmed progression of disease after an adjuvant therapy or a therapy for metastatic
disease with an aromatase inhibitors
6. Patients demonstrating prior response to AI therapy
7. Patients with measurable disease as per RECIST criteria /Patients with bone lesions,
lytic or mixed (lytic + sclerotic), in the absence of measurable disease as defined by
RECIST criteria.
8. May have received prior radiotherapy as treatment for primary or metastatic tumour;
however, is not required for study entry;
9. Life expectancy of at least 8 months
10. WHO performance status 0, 1 or 2
11. Patients with a history of other malignancies are eligible if they have been
disease-free for at least 5 years and are deemed by the investigator to be at low risk
for recurrence.
12. Are able to swallow and retain oral medication;
13. Are able to complete all screening assessments as outlined in the protocol;
14. Patients must have normal organ and marrow function
15. Left ventricular ejection fraction (LVEF) within the institutional normal range
Exclusion Criteria:
1. Previous therapy with Fulvestrant and/or Lapatinib;
2. Patients with HER 2 overexpressing, either IHC 3+ or FISH +;
3. Concurrent non study anti-cancer therapy (
4. Have unresolved or unstable, serious toxicity from prior administration
5. Have malabsorption syndrome,
6. Have a concurrent disease or condition that would make the patient inappropriate for
study participation,
7. Have an active or uncontrolled infection;
8. Have dementia, altered mental status, or any psychiatric condition that would prohibit
the understanding or rendering of informed consent;
9. Have a known history of uncontrolled or symptomatic angina, arrhythmias, or CHF;
10. Receive concurrent treatment with an investigational agent or participate in another
clinical trial;
11. Receive concurrent treatment with prohibited medications
12. Used an investigational drug within 30 days or 5 half-lives, whichever is longer,
preceding the first dose of study medication;
13. Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
chemically related to fulvestrant, aromatase inhibitors or lapatinib or excipients.
