Biology Reference
In-Depth Information
replication-associated DSB,
252
and possibly similar to the
toxic effects of 6-thioguanine.
benefit of platinum and other DNA damage inducing
therapies in BRCA1/2 mutant cancers, not only with
regard to tumor response but also response duration/
disease control as well as overall survival.
The association of
BRCA1
mutations and basal-like
phenotype has led to the assumption that sporadic
basal-like, triple-negative breast cancer involves
BRCA1 pathway dysfunction through epigenetic mech-
anisms, so that
BRCA1
-directed therapies would be
effective in this patient subset. However, a prospective
study from the Dana-Farber Cancer Institute in Boston
only observed a 22% pathological complete response
rate in a cohort of 28 patients with triple-negative
cancers treated with neoadjuvant cisplatin.
157
These
data are consistent with the notion that only a subset
of triple-negative cancers may be BRCA1 pathway defi-
cient and/or platinum sensitive. Randomized phase III
trials will need to formally address this question. For
example, the CALGB 40603 trial will examine the
benefit of adding carboplatin to taxane therapy in non-
metastatic triple-negative breast cancer. This study will
involve pre-treatment biopsies for predictive biomarker
evaluation to identify the subset of patients most likely
to benefit from carboplatin (see also “Biomarkers and
Clinical Translation” below).
Additional clinical data are emerging that correlate
BRCA pathway disruption, either via mutational mech-
anisms or reduced BRCA1 expression, with chemosensi-
tivity in several cancer types such as ovarian or lung
cancer.
177,178,258
However, despite the remarkably large
body of preclinical data, prospective clinical studies
remain scant. The main barrier to clinical translation
involves the need for predictive biomarkers to identify
those patients whose tumors harbor HRR defects and
are most likely to respond to DNA damaging agents
that target these defects. As chemotherapeutic agents
that cause replication fork collapse and induce HRR
are widely used in the treatment of multiple cancer
types, a better mechanistic understanding of the means
and genetic controls by which tumor cells repair
collapsed replication forks will be instrumental to the
development of rational treatment approaches that
translate into actual clinical benefit for patients.
Clinical Evidence for Chemosensitivity
of HRR-Deficient Cancers
What is the evidence that the abundance of laboratory
data on the chemosensitivity of HRR-deficient cancer
cells translates into clinical gain? The answer to this
question requires that the HRR status of a cancer is
known. However, as outlined above, not much is
currently known about the functional HRR status in
the majority of sporadic cancers, and the mutational or
expression status of a single HRR gene may not accu-
rately predict the overall activity of HRR in a cell.
Currently, the best clinical examples come from the
treatment of breast and ovarian cancers with defects in
the FA/BRCA pathway. Clinical evidence for the benefit
of PARP inhibitors is reviewed in Chapter 4.
Kennedy
et al.
summarized the clinical evidence to
determine whether BRCA1 or BRCA2 mutation status
correlates with chemosensitivity in breast cancer
patients.
253
Based on several retrospective studies, the
authors concluded that BRCA1 mutant status is associ-
ated with higher tumor response rates than wild-type
status. In 2008, Byrski
et al.
published the first prospective
study of 10 breast cancer patients with BRCA1 mutations
who were treated with induction cisplatin rather than
conventional chemotherapy.
254
Although these patients
had relatively limited stage tumors in terms of size and
absence of nodal involvement, strikingly 9 of the 10
patients experienced a pathological complete response.
In a follow-up retrospective analysis of 102 patients
with
BRCA1
germ line mutations treated with a variety
of neoadjuvant chemotherapy combinations, the cohort
of 12 patients receiving cisplatin had a pathological
complete response rate of 83% which compared to
approximately 20% or less for the other regimens.
255
While this retrospective analysis did have flaws, it has
provided important clinical evidence that fits the ample
pre-clinical data on the platinum sensitivity of BRCA1-
mutant cancer cells.
256
Because BRCA1/2 dysfunction
also confers sensitivity to topoisomerase II poisons and
possibly the crosslinker cyclophosphamide, these
tumors may also be sensitive to traditional anthracy-
cline-based and CMF (cyclophosphamide, methotrexate,
5-fluorouracile) chemotherapies. Kriege
et al.
recently
reported a retrospective matched analysis of 215 patients
with stage IV BRCA1/2 mutant breast cancers and
sporadic cancers treated with these chemotherapeutic
regimens.
257
As predicted, BRCA1/2 mutant tumors
demonstrated an increased clinical response rate
compared to sporadic cancers, i.e., 66
e
89% versus 50%
respectively, although the difference did not reach statis-
tical significance for the BRCA1mutant cancers. Prospec-
tive randomized trials are still needed to establish the
Exploiting HRR Defects for Radiation Therapy
Role of Radiation Therapy in Cancer Therapy
According to the National Cancer Institute, about half
of cancer patients receive some form of radiation
therapy during their lifetime. While radiation is respon-
sible for or contributes to high cure rates in many tumor
types, success rates for cancer types such as inoperable
lung cancer, glioblastoma multiforme, pancreatic cancer,
or advanced head and neck cancers are poor. In these
