In findings that are fundamentally reshaping the scientific understanding of breast cancer, researchers have identified four genetically distinct types of the cancer. And within those types, they found hallmark genetic changes that are driving many cancers.
These discoveries are expected to lead to new treatments with drugs already approved for cancers in other parts of the body and new ideas for more precise treatments aimed at genetic aberrations that now have no known treatment.
The study, published online on Sunday in the journal Nature, is the first comprehensive genetic analysis of breast cancer, which kills more than 35,000 women a year in the United States. The new paper, and several smaller recent studies, are electrifying the field.
“This is the road map for how we might cure breast cancer in the future,” said Dr. Matthew Ellis of Washington University, a researcher for the study.
“这是未来我们可能找到如何治愈乳腺癌的路线图，”华盛顿大学(Washington University)的马修·埃利斯(Matthew Ellis)博士说，他参与了这项研究。
Researchers and patient advocates caution that it will still take years to translate the new insights into transformative new treatments. Even within the four major types of breast cancer, 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 tailor medicines to individual tumors.
“There are a lot of steps that turn basic science into clinically meaningful results,” said Karuna Jaggar, executive director of Breast Cancer Action, an advocacy group. “It is the ‘stay tuned’ story.”
“将基础科学转化为有临床意义的成果需要很多步骤，”倡导团体乳腺癌行动(Breast Cancer Action)执行主管卡鲁纳·贾加尔(Karuna Jaggar)说。“这是个‘请继续关注’的故事。”
The study is part of a large federal project, the Cancer Genome Atlas, to build maps of genetic changes in common cancers. Reports on similar studies of lung and colon cancer have been published recently. The breast cancer study was based on an analysis of tumors from 825 patients.
本研究是美国联邦政府的大型项目、癌症基因组图谱(Cancer Genome Atlas)的一部分，项目旨在建立常见癌症的基因变异图谱。针对肺癌和结肠癌的类似研究结果已在早些时候发表。这次针对乳腺癌的研究来自对825名病人肿瘤的分析。
The study focused on the most common types of breast cancer that are thought to arise in the milk duct. It concentrated on early breast cancers that had not yet spread to other parts of the body in order to find genetic changes that could be attacked, stopping a cancer before it metastasized.
The study’s biggest surprise involved a particularly deadly breast cancer whose tumor cells resemble basal cells of the skin and sweat glands, which are present in the deepest layer of the skin. These breast basal cells form a scaffolding for milk duct cells. Such cancers are often called triple negative but the study researchers call them basal-like.
Basal-like cancers are most frequent in younger women, in African-Americans and in women with breast cancer genes BRCA1 and BRCA2.
And, the researchers report, their genetic derangements make these cancers a much closer kin of ovarian cancers than of other breast cancers. Basal-like breast cancers also resemble squamous cell cancer of the lung.
“It’s incredible,” said Dr. James Ingle of the Mayo Clinic, one of the study’s 348 authors, of the ovarian cancer connection. “It raises the possibility that there may be a common cause.”
研究论文的348名作者之一、梅约诊所(Mayo Clinic)的詹姆斯·英格尔博士(James Ingle)， 谈到与卵巢癌的关联时说，“真不敢相信。这提出了也许存在共同诱因的可能性。”
The study gives a biologic reason to try routine treatments for ovarian cancer — platinum drugs, for example — in basal-like breast cancer, the investigators said. And a common class of drug used in breast cancer, anthracyclines (adriamycin or epirubicin), might be dropped from the basal-like cancer treatment regimen because they do not increase help in ovarian cancer.
Anthracyclines, Dr. Ellis said, “are the drugs most breast cancer patients dread because they are associated with heart damage and leukemia.”
A new type of drug, PARP inhibitors, that seems to help squelch ovarian cancers, should also be tried in basal-like breast cancer, Dr. Ellis said.
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. Just about everyone with estrogen-fueled cancer gets the same treatment. Some do well. Others do not.
The genetic analysis divided luminal cancers into two distinct subtypes. The luminal A subtype had good prognoses while luminal B did not, suggesting that perhaps patients with luminal A tumors might do well with just hormonal therapy to block estrogen from spurring their cancers while luminal B patients 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, said Dr. Charles Perou of the University of North Carolina, who is the lead author of the study. And he called that “a stunning finding.”
该研究的主要作者、北卡罗来纳大学(University of North Carolina)的查尔斯·佩鲁(Charles Perou)说，在一些病例中，某些基因变异与两种腔细胞亚型中的一种或另一种的关联如此之强，以至于这些变异看来就是该亚型癌的确切诱因。佩鲁称这是“惊人的发现。”
“We are really getting at the roots of these cancers,” he said.
After basal-like cancers, and luminal A and B cancers, the fourth type of breast cancer is what the researchers called HER2-enriched. Breast cancers often have extra copies of a gene, HER2, that drives their growth. A drug, 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.
Yet although Herceptin is approved for every breast cancer patient whose tumor makes too much HER2, the new analysis finds that not all of these tumors are alike. The HER2-enriched should respond readily to Herceptin; the other type might not.
The only way to know is to do a clinical trial, and one is already being planned. Herceptin is expensive and can occasionally damage the heart. “We absolutely only want to give it to patients who can benefit,” Dr. Perou said.
For now, despite the tantalizing possibilities, patients will have to wait for clinical trials to see whether drugs that block the genetic aberrations can stop the cancers. And it could be a massive undertaking to get all the drug testing done. Because there are so many different ways a breast cancer cell can go awry, there may have to be dozens of drug studies, each focusing on a different genetic change.