open access: Nature Reviews: Key Advances in Medicine

CLINICAL ONCOLOGY
OVARIAN CANCER IN 2011
Mutations and non-inferiority analyses show
a way forward
Maurie Markman
Highly clinically relevant ovarian cancer clinical research in 2011 focused on an increased understanding of the
biology of the malignancy, limitations of strategies for early detection and screening, and the provocative reports of
alternative primary and second-line management strategies.
Markman, M. Nat. Rev. Clin. Oncol. 9, 69–70 (2012); published online 20 December 2011; doi:10.1038/nrclinonc.2011.200
Although there were a number of very interesting
preliminary reports of thera peutic
advances in ovarian cancer in 2011 (for
example, bevacizumab in the first-line and
second-line management of the malignancy,
and olaparib as maintenance therapy for
high-grade serous cancers), as of the writing
of this commentary these studies have not
appeared in the peer-reviewed oncology literature.
Despite the absence of major advances
in the realm of treatment, several papers
published in 2011 provide highly clinically
relevant insight into the management and
unique biology of ovarian cancer.
Perhaps the most important paper in
2011 was the long-awaited final report from
the Prostate, Lung, Colorectal and Ovarian
(PLCO) cancer screening randomized controlled
trial dealing specifically with ovarian
cancer. 1 The study, involving 78,000 women
with ages ranging from 55 to 74 years, randomly
assigned participants to what was
classified as ‘usual care’ or a rather-intensive
screening strategy that included annual
serum CA125 determinations and transvaginal
ultrasounds. It should be noted that
this study did not specifically target women
identified as being at ‘high risk’ for the
develop ment of ovarian cancer (for example,
those with a family history of ovarian cancer).
The screening protocol, undertaken from
November 1993 to July 2001, was performed
at one of 10 centers in the USA and the
median follow-up period for the population
was 12.4 years, with patients being followed
until death or for a maximum of 13 years.
The primary study end point was the rate
of mortality from ovarian cancer (including
primary peritoneal or fallopian tube cancer),
with secondary end points of disease incidence
and complications associ ated with
Table 1 | Influence of BRCA1 or BRCA2 on outcome in high-grade serous ovarian cancer 6
Mutational status 3-year
PFS (%)
5-year
PFS (%)
the screening strategy. The study revealed
no difference in deaths from ovarian cancer
or other causes between the screening and
usual-care groups. Specifically, there were
212 cases of ovarian cancer and 118 deaths
from the malignancy in the screening group
versus 176 cases and 100 deaths in the routine-care
population. Furthermore, and of
considerable relevance, 1,080 surgeries were
performed among the 3,285 women with
false-positive screening tests, and 163 of
these individuals developed at least a single
‘serious complication’. 1
The important data from this screening
trial provide no support for the routine use
of annual CA125 determinations or vaginal
ultrasounds for completely asymptomatic
women as a screening strategy to detect
ovarian cancer. However, it is again rele vant
to acknowledge that this trial did not specifically
address the issue of screening a more
high-risk population, nor did it attempt to
define the utility of these tests in the detection
of ovarian cancer in indivi duals presenting
with symptoms (for example, several
weeks of persistent mild abdominal pain).
A study that is somewhat related to the
PLCO trial attempted to address the important
question of whether an earlier diagnosis
of ovarian cancer in a sympto matic
individual might be associated with an
improved outcome. 2 Australian investigators
HR compared
with WT patients
3-year
OS (%)
5-year
OS (%)
HR compared
with WT patients
BRCA1 mutation 22 13 0.81 (P = 0.44) 64 44 0.76 (P = 0.35)
BRCA2 mutation 44 39 0.40 (P = 0.004) 83 61 0.33 (P = 0.003)
BRCA WT 16 10 – 58 25 –
Abbreviations: HR, hazard ratio; OS, overall survival; PFS, progression-free survival; WT, wild type.
retrospectively examined the survival of 1,300
patients with ovarian cancer seen by a physician
within varying time intervals (55%, 70%
and 92% of the women presented within 1,
2 and 6 months, respectively) from the onset
of their initial symptoms. The investigators
were unable to find any difference in survival
based on the duration of symptoms before
the time of diagnosis. Importantly, these data
do not support the hypothesis that a somewhat
earlier diagnosis (timeline measured
in ‘months’) will be associ ated with superior
ovarian cancer-specific survival, 3 although
the more-timely recognition of the correct
diagnosis will likely result in more-rapid initiation
of a management plan that will hopefully
favorably impact serious symptoms and
the individual’s overall quality of life.
It is well established that mutations in
BRCA1 and BRCA2 are associated with an
increased lifetime risk for the development
of ovarian cancer. 4 Furthermore, highly
provocative data from a number of ovarian
cancer investigators have suggested that
within the population of women with documented
advanced-stage ovarian cancer,
patients with BRCA mutations experience
an overall superior survival (compared with
patients with wild-type BRCA), a difference
that is possibly related to increased sensitivity
to platinum-based chemotherapy. 5 In
a most-provocative report, investigators
KEY ADVANCES IN MEDICINE JANUARY 2012 | S11