José Baselga, MD, PhD, medical oncologist at Memorial Sloan Kettering Cancer Center, discusses biomarker research for patients with breast cancer.

According to Baselga, the community is still in the process of validating some of the targets. There is a need to incorporate next-generation sequencing platforms into clinical practice.

It no longer makes sense to only check for estrogen receptor mutations or HER2 proliferation, but rather to look at comprehensive panels of genes. This will open opportunities for new ways to detect these abnormalities. For example, researchers are very excited by the prospect of developing liquid biopsies, which have the capacity to look for these DNA alterations in the blood. That would be a non-invasive approach, states Baselga.

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Dr. Baselga on Biomarker Research for Breast Cancer

José Baselga, MD, PhD, Physician-in-Chief, Memorial Sloan-Kettering Cancer Center (MSKCC), discusses the need to fine tune mTOR and PI3K inhibitor doses.

Fine tuning is an art, Baselga says, and takes place with all drugs, including chemotherapy. Dose and scale matter as a patient can see significant benefit increase with a finely tuned regimen. As an example, Baselga mentions paclitaxels, which can be given every three weeks or every week and demonstrate a big difference in terms of activity and side effects. Capecitabine can also be given on different scales: The one week on, one week off regimen developed at MSKCC, allows patients to stay on capecitabine for a far longer period of time.

In the case of mTOR inhibitors, evidence exists to support the notion that tailored therapy and decreased dosing can show similar benefit. Baselga says that physicians need to be open to tailoring therapies as much as possible.

JosÃ© Baselga, MD, PhD, Physician-in-Chief, Memorial Sloan-Kettering Cancer Center, discusses the need to fine tune mTOR and PI3K inhibitor doses.


Dr. Baselga Discusses Fine Tuning Drug Doses

JosÃ© Baselga, MD, PhD, Physician-in-Chief, Memorial Sloan-Kettering Cancer Center, discusses everolimus and the upcoming data from the BOLERO-3 trial in breast cancer.

In addition to the data regarding everolimus in ER-positive tumor, there is also evidence demonstrating that everolimus can enhance the effect of trastuzumab in patients with HER2-positive disease.

Data from the BOLERO-3 trial will be released soon, Baselga says. He is hopeful that the data will show benefit and provide another option for patients with HER2-positive disease.

Dr. Baselga Discusses Upcoming BOLERO-3 Data

José Baselga, MD, PhD, Physician-in-Chief, Memorial Sloan-Kettering Cancer Center, discusses treatment with PIK3CA inhibitors in patients with breast cancer.

Baselga says that PIK3CA inhibitors are very selective for cell lines that harbor the alpha mutation. Patients can often handle a higher dosage of this class of inhibitors as there is a different side effect profile, marking a potential advantage.

This subtype is sensitive to targeted agents, which allows for the blocking of the PIK3CA subunit very specifically.

JosÃ© Baselga, MD, PhD, Physician-in-Chief, Memorial Sloan-Kettering Cancer Center, discusses treatment with PIK3CA inhibitors in patients with breast cancer.

Dr. Baselga Discusses PIK3CA Inhibitors in Breast Cancer

José Baselga, MD, PhD, Physician-in-Chief, Memorial Sloan-Kettering Cancer Center, compares results from two trials analyzing the mTOR inhibitors temsirolimus and everolimus in breast cancer.

A phase II trial looked at a 25 mg/week dose of temsirolimus in patients with pretreated breast cancer who tested positive for ER, PR or HER2. The study found that temsirolimus as a single agent has minimal activity. However, the BOLERO-2 study that analyzed everolimus at 10 mg/day and exemestane at 25 mg/day for postmenopausal patients achieved its primary endpoint of progression-free survival.

Baselga says that the oncology community is trying to determine why temsirolimus and everolimus, both mTOR inhibitors, produced vastly different results in similar studies.

Baselga suggests that everolimus could only be working in patients with refractory disease. A more likely reason of the variance in results, according to Baselga, is dosing differences, which could explain the lower rate of mucositis in the temsirolimus study.

JosÃ© Baselga, MD, PhD, Physician-in-Chief, Memorial Sloan-Kettering Cancer Center, compares results from two trials analyzing the mTOR inhibitors temsirolimus and everolimus in breast cancer.

Dr. Baselga Compares mTOR Inhibitors in Breast Cancer

José Baselga, MD, PhD, Physician-in-Chief, Memorial Sloan-Kettering Cancer Center, discusses the investigation of pan-PI3K inhibitors for patients with metastatic breast cancer.

Following the success of mTOR inhibition in breast cancer, researchers are investigating the efficacy of blocking the PI3K/AKT/mTOR pathway further upstream. Baselga explains that initial pilot studies and early phase trials have shown promising activity for pan-PI3K inhibitors, which block the PI3K pathway directly at the PI3K molecule.

Larger registration studies are underway investigating pan-PI3K inhibitors for patients with breast cancer. The phase III BELLE-2 trial is currently enrolling postmenopausal patients with hormone receptor-positive, HER2-negative locally advanced or metastatic breast cancer that is refractory to aromatase inhibitors. This trial plans to randomize patients to receive either fulvestrant in combination with the PI3K inhibitor BKM120 or placebo.

Baselga notes that the patient population on this study is very similar to the BOLERO-2 trial that examined exemestane plus the mTOR inhibitor everolimus. The BELLE-2 trial plans to use fulvestrant instead of exemestane, since some believe fulvestrant is a superior hormonal therapy.

JosÃ© Baselga, MD, PhD, from Memorial Sloan-Kettering Cancer Center, discusses the investigation of pan-PI3K inhibitors for patients with metastatic breast cancer.


Dr. Baselga on pan-PI3K Inhibitors in Breast Cancer

José Baselga, MD, PhD, a professor in the Department of Medicine at Harvard Medical School and chief of Hematology/Oncology at Massachusetts General Hospital, discusses combining (Perjeta) with trastuzumab (Herceptin).

	The two antibodies work together because they have complementary mechanisms of action. HER2 signals via two main mechanisms, one of which is via ligand-independent HER2 activation. This mechanism is blocked by trastuzumab.

	Another activation of HER2 is the formation of dimers with other members of the HER2 family of receptors and, most importantly, with HER3. HER3 plays a critical role in HER2 signaling. The ligand binds to HER3, HER3 gets close to HER2, they dimerize, and they signal. This interaction is blocked by pertuzumab.

	By adding pertuzumab and trastuzumab together, the two known mechanisms of HER2 activation are blocked.

	The unique ability of pertuzumab plus trastuzumab to target HER2 led to the FDA approval of the combination with docetaxel on June 8, 2012, for  people with HER2-positive metastatic breast cancer who have not received prior therapy.

Dr. JosÃ© Baselga, from Massachusetts General Hospital, on combining pertuzumab with trastuzumab

Dr. Baselga on Combining Pertuzumab with Trastuzumab

José Baselga, MD, PhD, a professor in the Department of Medicine at Harvard Medical School and chief of Hematology/Oncology at Massachusetts General Hospital, describes the 3 phase III BOLERO trials investigating everolimus (Afinitor), a mammalian target of rapamycin inhibitor, in various stages of breast cancer.

		BOLERO-1 is still recruiting patients; it seeks to add first-line everolimus to trastuzumab (Herceptin) and paclitaxel in women with HER2-positive locally advanced or metastatic breast cancer.

		BOLERO-2 demonstrated the efficacy of adding everolimus to exemestane in women with aromatase inhibitor resistant, hormone receptor-positive, metastatic breast cancer. It successfully extended the time to disease progression by 4.2 months (HR, 0.44).

		BOLERO-3, which is still recruiting patients, will combine everolimus with trastuzumab and vinorelbine for post-menopausal HER2-positive breast cancer that is resistant to trastuzumab.

If the results from the BOLERO-1 and 3 trials are as positive as BOLERO-2 they will demonstrate the efficacy of everolimus in HER2-positive breast cancer, in both the first-line and refractory setting. BOLERO-2 was a second-line trial; Baselga feels a follow up study should include the first-line and adjuvant setting.

The findings of the BOLERO-2 trial go far beyond the patient population in the study. This research opens up the entire field of mTOR/PI3K-targeted therapies in multiple tumor types.

Dr. Jose Baselga from Massachusetts General Hospital Discusses the BOLERO Breast Cancer Trials

Dr. Baselga Discusses the BOLERO Breast Cancer Trials

José Baselga, MD, PhD, a professor in the Department of Medicine at Harvard Medical School and chief of Hematology/Oncology at Massachusetts General Hospital, discusses the clinical basis behind the success of the BOLERO-2 trial, which combined everolimus and exemestane in postmenopausal women with hormone receptor-positive breast cancer.

Baselga describes that data from multiple studies suggest that the mTOR pathway, which is downstream from PI3K and part of the PI3K/Akt/mTOR pathway, might play an important role in the formation of endocrine therapy resistance.

The mTOR pathway activates estrogen receptor (ER) transcription using the ribosomal protein S6. This type of activation can take place even in the ligand independent environment created by aromatase inhibitors (AIs). The ability to commence transcription without ligands results in AI resistance.

An initial neoadjuvant pilot study showed promising data suggesting that mTOR inhibition in combination with AIs could help stop resistance and proliferation. This information eventually led to the BOLERO-2 trial, which combined everolimus, an mTOR inhibitor, and exemestane, an AI.

Exemestane Plus Everolimus New Standard of Care for Postmenopausal Hormone Receptor-Positive Advanced Breast Cancer

Dr. Jose Baselga, from Massachusetts General Hospital, Describes the Basis Behind the BOLERO-2 Trial 

Dr. Baselga on the Basis Behind the BOLERO-2 Trial

José Baselga, MD, PhD, a professor in the Department of Medicine at Harvard Medical School and chief of Hematology/Oncology at Massachusetts General Hospital, explains that the phase III CLEOPATRA trial helped formally establish that dual HER2 blockade is superior to single agent inhibition with trastuzumab (Herceptin).

The trial randomly combined placebo or pertuzumab with trastuzumab and docetaxel in the first-line setting for patients with HER2-positive metastatic breast cancer. Other trials are underway to validate the relatively new concept of dual inhibition in adjuvant or early-stage breast cancer patients.

Baselga describes the idea of dual blockade as a conceptually broad transformation. The CLEOPATRA trial represents the key evidence needed to prove the efficacy of using two HER2 targeted agents together.

Dr. Jose Baselga from Massachusetts General Hospital Describes the Advantages of Dual Blockade

Dr. Baselga Describes the Advantages of Dual Blockade

José Baselga, MD, PhD, a professor in the Department of Medicine at Harvard Medical School and chief of Hematology/Oncology at Massachusetts General Hospital, describes the CLEOPATRA trial that examined the addition of pertuzumab for the first-line treatment of women with HER2-positive metastatic breast cancer.

CLEOPATRA was a randomized, phase III, placebo controlled trial with the primary endpoint of progression-free survival. The trial randomly combined placebo or pertuzumab with trastuzumab (Herceptin) and docetaxel. The control arm experienced disease progression at 12.4 months while the experimental arm did not progress until 18.5 months (HR = 0.62; 

The results of the trial were positive and although the survival data has not fully matured yet an interim analysis did show a very strong trend towards an overall survival benefit. The addition of pertuzumab entailed few additional side effects but did result in higher rates of diarrhea and neutropenia.

Baselga defines the trial as being a very positive first-line study for HER2 disease that is likely to become the standard of therapy for this patient population in the future.

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Jose Baselga, MD, PhD

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