317occurred at >10 % incidence across all breast cancers; however, there were numerous
subtype-associated and novel gene mutations including the enrichment of specifi c
mutations in GATA3, PIK3CA and MAP3K1 with the luminal A subtype. Two
novel protein-expression-defi ned subgroups were identifi ed, possibly produced by
stromal/microenvironmental elements, and integrated analyses identifi ed specifi c
signaling pathways dominant in each molecular subtype including a HER2/phos-
phorylated HER2/EGFR/phosphorylated EGFR signature within the HER2-
enriched expression subtype. Comparison of basal-like breast tumors with
high-grade serous ovarian tumors showed many molecular features common to both
cancers, indicating a related etiology and similar therapeutic opportunities. The bio-
logical fi nding of the four main breast cancer subtypes caused by different subsets
of genetic and epigenetic abnormalities leads to the hypothesis that much of the
clinically observable plasticity and heterogeneity occurs within, and not across,
these major biological subtypes of breast cancer. This is the road map for how breast
cancer might be cured in the future. Even within the four major types of breast can-
cer, individual tumors appear to be driven by their own sets of genetic changes.
A wide variety of drugs will most likely need to be developed to be specifi cally
effective for individual tumors. For example, PARP inhibitors that seem to be effec-
tive against ovarian cancers, may also be tried in basal-like breast cancer, which are
most prevalent in younger women, in African-Americans and in women with breast
cancer genes BRCA1 and BRCA2. Two other types of breast cancer, accounting for
most cases of the disease, arise from the luminal cells that line milk ducts. These
cancers have proteins on their surfaces that grab estrogen, fueling their growth.
Genetic analysis divided these cancers into two distinct types. Patients with luminal
A cancer had good prognoses while those with luminal B did not, suggesting that
perhaps patients with the fi rst kind of tumor might do well with just hormonal ther-
apy to block estrogen from spurring their cancers while those with the second kind
might do better with chemotherapy in addition to hormonal therapy. In some cases,
genetic aberrations were so strongly associated with one or the other luminal
subtype that they appeared to be the actual cause of the cancer. After basal-like
cancers, and luminal A and B cancers, the fourth type of breast cancer frequently
has extra copies of HER2 gene that drives their growth. Herceptin, can block the
gene and has changed the prognosis for these patients from one of the worst in
breast cancer to one of the best. Although Herceptin is approved for HER2 positive
breast cancer patients, the new analysis fi nds that not all of these tumors are alike in
responding to it. This is being investigated in further clinical trials.
This study demonstrates benefi ts of integrating genomic and proteomic data, par-
ticularly phosphoproteomics, which provided information beyond what the gene
expression could. Proteomic data suggests the existence of two distinct
phosphoproteomic- based subtypes within the larger gene expression-based HER2
subtype − one exhibiting high HER2 and HER1 signaling activity and the other
exhibiting lower levels of such activity. The other example where the protein made
one think was the analysis of PI3 kinase signaling, in which a disconnect was found
between the PI3K signaling data obtained via the reverse-phase protein arrays anal-
ysis and their PI3K mutation data. A pathway-based analysis of the PI3K signaling
Personalized Management of Cancers of Various Organs