2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

TREATMENT OF ADVANCED BREAST CANCER
option. New trials represent an important source of hope–
and offer potential therapeutic benefit–for patients with
advanced breast cancer. The National Institutes of Health’s
clinicaltrials.gov website represents an invaluable resource
in this regard.
A Good Death
Because MBC is generally incurable, it is important for
physicians to be honest with patients regarding their prognosis,
particularly as treatment options dwindle. Advanced
care planning should be part of a physician’s discussion with
patients. Appropriate end-of-life care includes the discussion
of hospice care as a therapeutic option. The American
Society of Clinical Oncology’s Advanced Care Planning booklet,
available freely through its Cancer.net website, is a good
starting point for patients with MBC.
Treatment Past: Lessons Learned, but Let’s Move On
One of the major criticisms raised nowadays of the “older”
clinical trials is the fact that most of them were run in
“all-comers” without a biologic-based patient selection. However,
it was in the metastatic setting where the first targeted
trials were conducted. Our oldest form of targeted therapy–
endocrine therapy–was first used in MBC patients. The
understanding of the crucial predictive role of the estrogen
receptor (ER) led to selection based on ER status. The first
studies of the anti-HER2 agent trastuzumab were performed
in patients with MBC selected by HER2 receptor
status. In the trials of cytotoxic agents, patient selection
according to biology is only a recent phenomenon.
Multidisciplinary and Locoregional Treatments
An important change in oncology occurred with the understanding
of the crucial role of a multidisciplinary approach
to cancer treatment, with active cooperation among all
specialists involved in the care of these patients. Unfortunately,
this multidisciplinary approach is often forgotten in
the advanced setting. With the development of efficacious
locoregional treatments to several types of metastases
(mainly brain, bone, and liver) the multimodal approach has
become more prominent.
Many unanswered questions remain–the role of locoregional
therapy of the primary cancer for patients diagnosed
with stage IV breast cancer (a survival benefit is suggested
KEY POINTS
● The goals of care in metastatic breast cancer (MBC)
include cure, prolongation of survival, palliation of
symptoms, development of new agents, and a good
death.
● The roots of targeted therapy lie in past decades of
clinical trials.
● These trials also did much to elucidate the proper role
of systemic chemotherapy regimens in MBC.
● Current treatment approaches are based on the
proper use of knowledge regarding growth factor
receptors (estrogen receptor and HER2).
● Novel treatments for MBC attack increasing portions
of the “hallmarks of cancer.”
by retrospective series, 9 and there are three ongoing trials);
the best candidates, timing, and approach (surgery, radiofrequency,
a combination of both) for liver and lung metastases;
and the best sequence of therapies for brain
metastases (surgery, radiotherapy, radio-surgery, combination
with a systemic therapy).
Systemic Therapy: Best Endpoints, Survival Benefits
Though many new agents have been developed and incorporated
into the treatment of MBC, very few provided a
survival benefit, 10 and when they did, it was almost exclusively
as first-line therapy (doxorubicin � paclitaxel vs.
5-FU � doxorubicin � cyclophosphamide; letrozole vs. tamoxifen)
or when compared with very old and abandoned
drugs (i.e., melphalan or mitomycin plus vinblastine) or in
trials that compared combination regimens with single
agents, although neglecting planned cross-over (docetaxel �
capecitabine vs. docetaxel alone or paclitaxel � gemcitabine
vs. paclitaxel alone).
Although OS benefit is undoubtedly the most desired
outcome, progression-free survival (PFS) has been the most
widely used endpoint. However, it is not a good surrogate for
OS benefit, 11 and no good surrogate has yet been developed.
Heated discussions regarding the merits of OS or PFS as the
most adequate endpoint are ongoing, as is the incorporation
of validated quality-of-life measurements and patientreported
outcomes.
Endocrine Therapy (ET): Optimal Agents and Optimal Sequence
of Therapies
For ER-positive premenopausal women, some relatively
small trials and a meta-analysis found statistically significant
survival benefits with third-generation aromatase inhibitors
(AIs) (letrozole, exemestane, and anastrozole)
(relative hazard (RH) � 0.87, CI 95%: 0.82 to 0.93; p �
0.001). In first-line trials, in which AIs were compared with
tamoxifen, the survival benefit was of 11% RH reduction
(95% CI: 1% to 19%; p � 0.03). Their benefit in second and
subsequent line trials, in which they were compared with
other treatments, was similar. 12 However, these trials have
been performed in a era when tamoxifen was the gold
standard adjuvant ET, and currently the great majority of
postmenopausal women receives an AI in the adjuvant
setting. Trials in MBC patients pretreated with AIs have
shown that another AI, fulvestrant, and tamoxifen are
viable options at progression.
For ER-positive premenopausal women, tamoxifen with or
without ovarian suppression/ablation (OS/OA) has remained
the standard adjuvant therapy, and some relatively small
trials and a meta-analysis provide evidence that for first-line
therapy for MBC ER-positive premenopausal patients, the
combination of OS/OA with tamoxifen is superior to tamoxifen
alone. Although frequently used in the clinic, the
combination OS/OA with an AI has not been properly
evaluated in the metastatic setting, and, unfortunately,
randomized trials of fulvestrant for MBC have not included
premenopausal women.
Chemotherapy: Optimal Drug/Regimen for First, Second, and More
Lines of Therapy; Combination Versus Sequential Monotherapy;
Optimal Sequence of Drugs
One of the most challenging and controversial issues in
MBC treatment relates to chemotherapy use. Almost all
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