Chemo is never recommended for DCIS, unless there is invasive cancer with it. Radiation therapy is also rarely (if ever) recommended or indicated after bilateral mastectomy for DCIS, unless the surgical margins are grossly positive and the surgeon feels that re-excision to get clean margins is impossible.

Based on preclinical work (work with cancer cells in a petri dish), lapatinib and trastuzumab act synergistically when combined (meaning they make each other work better so 1+1 doesn’t equal 2, it equals 3). A phase III trial evaluating patients with HER2+ metastatic breast cancer who had received multiple lines of trastuzumab-based chemotherapy was reported that compared lapatinib alone to lapatinib plus trastuzumab. This study showed that continuing trastuzumab (even though patients had all received trastuzumab and their disease had grown on it previously) led to a longer progression free survival and overall survival. In the early breast cancer setting, when given prior to surgery (neoadjuvant) lapatinib plus trastuzumab has been shown to be better than lapatinib or trastuzumab alone in terms of tumor response to therapy. In the adjuvant setting (after surgery), a large study called ALLTO, is evaluating lapatinib plus trastuzumab vs lapatinib vs trastuzumab. The lapatinib single agent arm was stopped early because it appears to be less effective than the other two arms. The results of that study have not yet been reported.

Recently, a phase III trial called EMILIA was reported. This study randomly assigned patients to receive T-DM1 or lapatinib/capecitabine for treatment of HER2+, trastuzumab-pretreated metastatic breast cancer. The study showed that TDM1 is better tolerated and is associated with a longer progression free survival (meaning, patients taking TDM1 live longer without their disease growing). This is exciting data that will likely lead to the FDA approval of this medicine in the US this year.

There are multiple new exciting agents for HER2 positive breast cancer. Currently, the only FDA approved therapies are trastuzumab and lapatinib (lapatinib only approved for stage IV cancer currently).

A new agent called trastuzumab emtansine (T-DM1) is very promising-with phase III results presented a week ago at ASCO. This drug is trastuzumab linked to a toxic chemotherapy—the trastuzumab delivers the chemotherapy directly to the cancer cell, thereby relatively sparing normal cells. The positive results presented this month at ASCO will hopefully lead to FDA approval of this drug shortly.

Another antibody-based therapy that showed excellent phase III results in combination with trastuzumab and docetaxel is pertuzumab. This drug should also be approved in the coming months.

Small molecule tyrosine kinase inhibitors (like lapatinib) are also being developed that strongly inhibit HER2 and other targets (HER1, HER3, HER4). One such drug is afatinib—this drug is in phase III testing now and is very promising given its potent inhibition of the targets. Molecules that target the PI3K-AKT-MTOR pathway that is implicated in treatment resistance in HER2+ breast cancer are also being evaluated in phase III trials and include drugs such as everolimus.

There are many targets being identified in breast cancer that are very promising for the development of biologically targeted therapy. With many targeted therapies, we are seeing the development of treatment resistance, as the tumor cell adapts to having one target turned off and turns another “driving force” pathway in its place to ensure its survival. Because of this problem, multi-targeted therapies are being evaluated and developed to try to combat treatment resistance.

The classification of breast cancer is evolving. Historically, we classified breast cancers based on how they appear under the microscope and what growth patterns they make. This classification system is called “histological” and includes invasive ductal carcinoma, invasive lobular carcinoma and multiple other rarer types of breast cancer (medullary, mucinous, tubular, etc). This classification system does not provide much information regarding what the driving force of the cancer is, does not tell us what type of therapy is going to be most effective, and does not tell us much about prognsosis. In the last 3 decades, a more molecular classification has emerged (and continues to be refined). In the clinic, we now roughly classify tumors by the types of proteins the tumor expresses, including HER2, and the hormone receptors (ER and PR). This gives us more information about prognosis and guides treatment choices. For example, a tumor that is positive for ER and PR, negative for HER2 and is small, the best treatment after surgery/radiation is anti-hormonal therapy (tamoxifen and/or an aromatase inhibitor). Tumors that lack expression of all three proteins are termed “triple negative” and tend to be more aggressive, often requiring chemotherapy. Inflammatory breast cancer is a clinical diagnosis (not a molecular or histological diagnosis) that is made when a patient has a very rapid development (days to weeks) of a red, hot, swollen breast. It is rare (1% of all breast cancer) and is most commonly HER2+ or triple negative and requires urgent treatment with chemotherapy.

Targeted therapies are medicines that are designed to specifically kill a cancer cell, while relatively sparing normal cells. In order to develop a targeted therapy, one must understand (1) what is making the tumor cell behave “badly,” for example-what is occurring inside the tumor cell that makes it divide too often and (2) what is unique about the tumor cell (compared to a normal cell). Sometimes there is one molecule or protein that is expressed in the tumor cell that is the “driving force” of the tumor’s behavior. When that “driving force” is identified, scientists can then develop a drug that specifically targets that molecule to block its activity. A famous example of this is HER2. Approximately 20-25% of breast cancers have too much of the HER2 protein expressed on the cell surface (because the tumor cell makes too many copies of the gene that encodes for HER2). In the 1980s, it was shown that this type of breast cancer (HER2+) was associated with a worse prognosis and it was also shown that the HER2 protein makes the cell behave particularly aggressively. With the understanding that HER2 is the “driving force” for this type of cancer, scientists went on to develop an antibody therapy (trastuzumab, or Herceptin) that specifically attaches to the HER2 protein on the tumor cells and stops the activity of HER2, leading to tumor cell death. Trastuzumab is thus a therapy that targets HER2.

The current standard of care is 1 year (based on the large randomized clinical trials in non-metastatic breast cancer). We do not know if less than one year is as effective (studies are ongoing to address that such as PHARE study which is comparing 6 mos to 1 year) or whether longer therapy is better (HERA study is evaluating 1 versus 2 years of therapy).