Neoplasms

Skin and Connective Tissue Diseases

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Breast Neoplasms

Breast Diseases

Skin Diseases

Antineoplastic Agents

All Drugs and Chemicals

Amino Acids

Trastuzumab

Hormones

Letrozole

Estrogens

Lapatinib

Progesterone

Antineoplastic Agents, Immunological

Aromatase Inhibitors

Enzyme Inhibitors

Estrogen Antagonists

Estrogen Receptor Antagonists

Hormone Antagonists

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Tyrosine

Participants will receive 24-weeks of lapatinib plus trastuzumab. Participants who are estrogen receptor (ER) and/or progesterone receptor (PR) positive will also receive endocrine therapy.

Participants will receive 12-weeks of lapatinib plus trastuzumab. Participants who are estrogen receptor (ER) and/or progesterone receptor (PR) positive will also receive endocrine therapy.

Letrozole, 2.5 mg by mouth daily (for hormone receptor positive participants only)

Mothaffar Rimawi, MD

Breast cancer is the most common malignancy in the U.S. Targeted therapies such as tamoxifen have been revolutionary in reducing tumor recurrences and mortality in early breast cancer. Using this successful paradigm, there has been a continued search for other targeted biologic therapies directed at receptors with known potential for promoting tumor growth.

The estrogen receptor (ER) and/or the HER signaling pathways are the dominant drivers of cell proliferation and survival in the majority of human breast cancers. Molecular targets of these pathways provide the most effective therapies in appropriately selected patients. However, de novo and acquired resistance remain major obstacles to successful treatment, and understanding the molecular pathways responsible for this resistance would enable the discovery of new strategies to overcome it.

The superiority of multi-drug HER2-targeted therapy over single agent therapy has been demonstrated in the preclinical setting using mouse xenografts. Trastuzumab, pertuzumab, lapatinib, and gefitinib, represent a group of therapeutic agents that target the HER family by different molecular mechanisms. Used as single agents in the MCF7/HER2-18 xenograft model, these drugs restored or enhanced sensitivity to tamoxifen. However, tumor growth inhibition lasted only 2-3 months before resistance to treatments occurred. However, when gefitinib, a HER1 inhibitor, was added to the two-antibody (T+P) regimen to block signals from HER1 dimers, a complete disappearance of nearly all xenograft tumors was observed; moreover, there was evidence of complete tumor eradication in 50% of the mice. The combination of lapatinib + trastuzumab was also highly effective in eradication of tumor burden, with no evidence of re-growth after 200 days. These xenograft models demonstrate that multi-drug HER2-targeted therapy more effectively induces apoptosis and inhibits proliferation, thereby resulting in tumor regression. Furthermore, HER2 combination therapy appears to more effectively reduce levels of phosphorylated pAKT and MAPK, thus resulting in sustained tumor inhibition.

Breast cancer cells have certain characteristics or traits--these traits are called biomarkers. There are three biomarkers that help doctors decide which treatment to give any given patient. These biomarkers are the estrogen receptor (ER), progesterone receptor (PgR), and HER2 protein. Breast cancer cells that have a large number of estrogen or progesterone receptors are called ER and/or PgR positive. Cancers that are ER and/or PgR positive use the hormones estrogen and progesterone to help them grow. Not all breast cancers are ER or PgR positive. Patients are being asked to take part in this study that have a special type of breast cancer called HER2 positive breast cancer. HER2-positive breast cancer is a breast cancer that tests positive for a protein called human epidermal growth factor receptor-2 (HER2). HER2 is located on the outer surface of a cancer cell. The HER2 protein sends a signal to the inside of the cancer cells telling it to grow and divide.

Two medications that directly target this HER2 protein. One is called trastuzumab(Herceptin), and the other is called lapatinib (Tykerb). Both medications are FDA-approved for the treatment of women with HER2+ breast cancer. Each medication attaches to the protein so that it can no longer function. Once the protein stops working, the cancer cells can no longer make copies of themselves. This makes cancer shrink. Both drugs target HER2; however each drug works a little bit differently.

Some patients respond better to Herceptin, and some patients respond better to Tykerb. Right now, we are not sure why some patients respond to one drug but do not respond to the other drug. One possibility is that in some patients, the HER2 protein finds another way to send its message to the inside of the cell (similar to a road detour). For example, when one path is "closed" because the drug is blocking it, the HER2 protein finds a different way to send its signal. We think that we can completely block the HER2 protein by giving patients both Tykerb and Herceptin.

Some patients with HER positive breast cancer are also ER and/or PgR positive. Even after HER2 is completely blocked, these types of cancer cells can still grow by using the estrogen or progesterone receptor. If a patient is told they are ER and/or PgR positive, they will also take an anti-estrogen pill along with Tykerb and Herceptin. We think that we can stop cancer growth more completely by blocking both the HER2 protein and the ER/PR receptors.

Extension Study of Lapatinib Plus Herceptin With or Without Endocrine Therapy

TBCRC 023: A Randomized Multicenter Phase II Neoadjuvant Trial of Lapatinib Pus Trastuzumab, With or Without Endocrine Therapy for 12 Weeks vs. 24 Weeks in Patients With HER2 Overexpressing Breast Cancer

Pathologic complete response was defined as no residual invasive cancer in the breast, after 12 or 24 weeks of lapatinib/trastuzumab with or without endocrine therapy.

This outcome is based on patient's pathological report. We are not measuring the clinical response.

Participants who have received at least one cycle of therapy (defined as one dose of trastuzumab and 21 days of lapatinib), and have had their response classified were evaluable.

the safety and tolerability of an extended regimen of lapatinib + trastuzumab, with or without endocrine therapy

pathologic complete response was defined as no residual invasive cancer in the breast and the axillary lymph nodes.

Translational Breast Cancer Research Consortium

GlaxoSmithKline

Baylor Breast Care Center

Professor

Adverse events experienced by participants will be collected and reported from initiation of study medication, throughout the study, and within 30 days of the last dose of study medication.

Participants will receive 24-weeks of lapatinib plus trastuzumab. Participants who are estrogen receptor (ER) and/or progesterone receptor (PR) positive will also receive endocrine therapy.

Lapatinib: 1000 mg by mouth daily

Letrozole: 2.5 mg by mouth daily (for hormone receptor positive participants only)

Trastuzumab: 6 mg/kg intravenously, every 3 weeks

24-week Arm

Participants will receive 12-weeks of lapatinib plus trastuzumab. Participants who are estrogen receptor (ER) and/or progesterone receptor (PR) positive will also receive endocrine therapy.

Lapatinib: 1000 mg by mouth daily

Letrozole: 2.5 mg by mouth daily (for hormone receptor positive participants only)

Trastuzumab: 6 mg/kg intravenously, every 3 weeks

12-week Arm

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Dr. Mothaffar Rimawi

The study was planned to enroll 136 patients if the original cohort (n=90) was deemed successful. The 24 weeks arm ran as a single arm, using an admissible Simon-like two-stage design. The 12 weeks arm accrued as long as the 24 weeks arm is open.

The analysis of the first cohort indicated that 15 pCR were observed , which did not meet the required 20 or more responses. The accrual was closed early and the study has a total of 128 participants.

pathologic complete response

non-complete pathologic response

Participants who have received at least one cycle of therapy (defined as one dose of trastuzumab and 21 days of lapatinib), and have had their response classified were evaluable. 4 participant were not evaluable: 3 participant were found ineligible for the study and one participant died before surgery.

Pathologic Complete Response

This outcome is to establish the safety and tolerability of an extended regimen of lapatinib + trastuzumab, with or without endocrine therapy. No comparison between the 2 arms is required.

Participants who started the study treatment will be evaluable for safety analysis

Number of Participants With Adverse Events

No comparison between the two arms is required.

total complete pathologic response

not total complete pathologic response

Total Pathologic Complete Response

No comparison between the 2 arm is required for this study.

Complete response

Partial response

Stable disease

Progressive disease

Unknown

Participants who have received at least one cycle of therapy (defined as one dose of trastuzumab and 21 days of lapatinib), and have had their response classified were evaluable. 4 participants were not evaluable for efficacy.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Extension Study of Lapatinib Plus Herceptin With or Without Endocrine Therapy	NCT00999804	Breast Cancer	Lapatinib Letrozole Trastuzumab	18 Years -	Baylor Breast Care Center
Extension Study of Lapatinib Plus Herceptin With or Without Endocrine Therapy	NCT00999804	Breast Cancer	Lapatinib Letrozole Trastuzumab	18 Years -	Baylor Breast Care Center

Spots Global Cancer Trial Database for locally advanced breast cancer neoadjuvant endocrine