Breast Cancer Management: Novel Therapies and Future Trends


NEW TRENDS OF TARGETED THERAPY AND IMMUNOTHERAPY IN BREAST CANCER

Archara Supavavej

Chulabhorn Hospital, Princess Chulabhorn College of Medical Science, Chulabhorn Royal Academy, Bangkok, Thailand


SYNOPSIS

Her2 positive breast cancer is the first example of targeted therapy in breast cancer treatment. In 1998, Trastuzumab, a humanized monoclonal antibody targeted at the extracellular domain of the transmembrane receptor Her2, was first approved for treatment of Her-2 positive metastatic breast cancer.Her2 and Her-3 dimerization was the second target for Her2 positive breast cancer. Pertuzumab combined with Trastuzumab was the comprehensive Her2 dual blockade. Cleopatra study reported significantly improved both progression free survival and overall survival with Pertuzumab plus Trastuzumab plus Docetaxel compared with Trastuzumab plus Docetaxel. Consequently, Pertuzumab in combination with trastuzumab and Docetaxel became the standard of care for the first line for recurrent/metastatic Her2 positive breast cancer since 2012.

Lapatinib, reversible EGFR (Her1) and Her2 dual Tyrosine kinase inhibitor, in combination with capecitabine was superior to capecitabine alone in Her2 positive advanced breast cancer that progressed after anthracycline, taxanes and trastuzumab as EGF104900. Six year later, Trastuzumab emtansine-1 (T-DM-1), Anti-Her2 Antibody (Trastuzumab) drug conjugated with Emtansine classified as tubulin inhibitors, could improve both the progression free survival and the overall survival to lapatinib plus capecitabine as EMILIA study in 2013. To date, T-DM-1 was approved for the second line for Her2 positive recurrent/metastasis breast cancer.

In setting of adjuvant therapy, Hera study was published in 2006. One year after adjuvant Trastuzumab was approved for treatment of Her-2 positive early breast cancer. In 2011, Concurrent Trastuzumab with chemotherapy became the standard of care for Her2 positive in early breast cancer as Joint analysis data of NCCTG N-9831 and NSABP B-31. Pertuzumab and trastuzumab can improved disease free survival above trastuzumab alone in APHINITY trial.T-DM-1 was also approved for residual Her2 positive early breast cancer after Neoadjuvant chemotherapy plus anti-Her2 drug and surgery as Katharine study in 2019. Neratinib, an irreversible Pan Her (EGFR, Her2 and Her 4) receptor tyrosine kinase inhibitor, demonstrated benefit of extended 1 year of adjuvant Neratinib after completion of adjuvant trastuzumab for  1 year with moderate adverse effects.

Triple negative breast cancer (TNBC) is another subtype of breast cancer that never has targeted treatment in the last two decades. Until now there have been three novel targets for TNBC. To begin with PARP (Poly ADP Ribose Polymerase) inhibitor, the second is Androgen receptor blockade and the last is Immune checkpoint inhibitors.

PARP inhibitor has an activity in BRCA gene related cancer such as ovarian cancer or breast cancer. Most common subtype of BRCA1/2 related breast cancer was triple negative breast cancer. Loss of function of BRCA gene resulted in defective homologous recombination. Synthetic lethality can be achieved when using PARP inhibitors in this setting. Concurrent tumor intrinsic BRCA loss of function and pharmacologic PARP inhibition effects tumor cell death with high therapeutic index. Olympiad is the first phase III study of Olaparib in advanced Her2 negative breast cancer with BRCA gene mutation with prior two chemotherapy regimens and was presented in ASCO 2017. Olaparib improved progression free survival significant compared to standard of care chemotherapy. Subgroup of triple negative breast cancer had more significant benefit above Hormone positive Her2 negative breast cancer. Talazoparib is the second drug approved in advanced Her2 negative breast cancer with BRCA gene mutation as the result of EMBRACA study in 2018. Both studies provided the undistinguishable results. 

Androgen Receptor blockade is the second target of TNBC treatment. Luminal androgen receptor subtype was identified in TNBC from Gene expression microarray based studies; there is a high expression of androgen receptor messenger RNA in addition to downstream Androgen Receptor targets and co activators. Androgen receptor inhibition was postulated for antitumor activity. Abiraterone and Enzalutamide were studied in phase II clinical trials. Both provided impressive results with 6 months clinical benefit rate of 20% and 29%, respectively. The ENDEAR study, Phase III clinical trial of Enzalutamide was initiated in 2016.

Immune checkpoint inhibitor was mentioned in TNBC due to twenty percent of triple negative breast cancer has immunomodulatory subtype which expressed genes that involved in immune systems. Early stage Triple negative breast cancer has high levels of tumor infiltrating lymphocytes (TILs) which represented better prognosis. TILs significantly contribute gene expression profile and present immune checkpoint gene such as Program cell Death 1 (PD-1) and Program cell Death Ligand 1 (PD-L1). T-cell checkpoint inhibitor promotes antitumor immune response and has an impressive efficacy data across many tumor types including TNBC.

Pembrolizumab ,anti-PD-1 checkpoint inhibitor , Monotherapy has an overall response rate of 18.5% in multicohort phase 1B study for PD-L1 positive metastatic TNBC. Phase II study (Keynote 086) preliminary reported Pembrolizumab as the first line treatment of metastatic TNBC provided the overall response rate 23% with  three patients achieved complete response. Phase III study of Pembrolizumab monotherapy in previously treated metastatic TNBC (Keynote 119) was completely recruited by the end of 2017. Atezolizumab , anti-PD-L1 checkpoint inhibitor, as a single agent in phase IA showed efficacy in metastatic TNBC with an overall response rate of 33%.

Combination of chemotherapy and immunotherapy may be promising in TNBC. Chemotherapy can enhance immune response to cancer and synergize with immunotherapy. Phase I B study of Atezolizumab plus Nab paclitaxel showed promising data in the first line metastatic TNBC with 71% of overall response rate. Phase III study of Atezolizumab and Nab Paclitaxel (Impassion 130)  showed significant improved progression free survival in all TNBC and PD-L1 positive groups. So it was approved as the first line treatment of metastatic TNBC.

The Future trends of targeted therapy and immunotherapy still have many ongoing clinical studies. Immune checkpoint inhibitor can change the paradigm of TNBC treatment in the next few years.


ADVANCED IN BREAST CANCER RADIOTHERAPY

Kitwadee Saksornchai, MD

Division of Therapeutic Radiology and Oncology, Department of Radiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand


SYNOPSIS

In the early era of the breast cancer radiotherapy, the radiotherapy was done by a fluoroscopic simulator in two dimensional images (X-ray) using bony outline that’s  difficult to verify the location of the tumor and the exact radiation dose to nearby organ tissue. Many years later, the computed tomography (CT) imaging had been developed and implemented in the radiotherapy. With CT planning, we are able to identify the location of tumors and organs at risk. We can assure the target coverage and dose distribution.

The novel techniques such as intensity modulated radiotherapy (IMRT) or volumetric modulated radiotherapy (VMAT) ( have been approved in terms of conformality achievement to the target volume and dose reduction to normal nearby organs such as lungs and heart in the breast cancer radiotherapy.

The late toxicity from breast irradiation such as cardiotoxicity has been becoming a concern. A study from Darby showed that the risk of major coronary events increased 7.4% per 1 gray of the median heart dose. Many techniques have been applied to reduce the heart dose. For example, prone position has been favored in patients with pendulous breasts and provided significantly lower in the lung and heart doses. Deep inspiration breath hold (DIBH) ()allowed the large distance between the chest wall and the heart and  associated with significant improvement in heart dose. However, this technique could be used in patients who are able to hold their breathing during the treatment. 

Furthermore, the  shortening time of treatment has also been proposed in terms of time reduction and breast tumor biology.  ASTRO guideline 2018 has recommended that hypofractionation can be used in the whole breast irradiation both in ductal carcinoma in situ and invasive cancer. Partial breast irradiation is an alternative treatment for selected low risk patients. 

Finally, the  proton therapy which is a particle beam therapy in breast irradiation is feasible without excessive toxicities and significantly improves lung and cardiac dose, especially in left sided patients.

In conclusion, the radiation technique in breast irradiation has immensely progressed over the years. All of those techniques are personalized tumor dose distribution with lowest normal organ.


RECENT ADVANCE AND FUTURE TRENDS IN THERAPY FOR HORMONE RECEPTOR POSITIVE BREAST CANCER

Assistant Professor Thitiya Dejthevaporn MD

Medical Oncology Unit, Department of Internal Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand


SYNOPSIS

Approximately two-thirds of breast cancers are hormone receptor (HR) positive. Although many patients diagnosed with early stage disease are cured, HR positive tumors are notorious for a lifelong relapse risk that is unpredictable. Once recurrence occurs, it is unlikely to be cured. Endocrine therapy has been the mainstay of treatment and it plays a crucial role of maintaining disease control, delaying the need for chemotherapy, and preserving quality of life. In general, in the absence of a visceral crisis, two to four lines of endocrine therapy (ET) may be attempted before resorting to cytotoxic chemotherapy. Historically, median survival of patients with HR positive MBC has been reported to range between 16 and 26 months. Both de novo and acquired resistance to initial ET lead to endocrine resistance. Several mechanism of resistance have been identified such as ESR 1 mutation, upregulation of the growth and survival pathway, phosphoinositide 3-kinase (PI3K)/Akt/mTOR, cyclin D1 overexpression, and HER2 overexpression. Recently, a changing concept of treatment from sequential single agent therapy to combination therapy is evident based on an improvement in understanding of pathway activation and treatment resistance. However, optimal sequencing of these therapies is evolving. Although each of these combinations improves progression-free survival, none with the exception of anastrazole plus fulvestrant have demonstrated improved overall survival. Moreover, they are associated with an increased risk of potentially serious and early‐onset class‐specific toxicities which would require closer monitoring and patient education. 

Improved biomarkers to better identify and eventually be able to individually select patients for given treatments on the basis of accurate prediction of response and resistance are important subjects of current and future research efforts. 

For conclusion, tremendous efforts to understand the biological mechanisms of hormone therapy resistance, with the ultimate goal of implementing new therapeutic strategies to improve the current treatments for ER positive breast cancer are ongoing. Novel drugs and combination therapy have proven benefit but more researches are needed to further optimize patients’ outcome.

Event Hours(1)

  • Lotus 5-6

    01:00 pm – 02:15 pm

    Speakers:
    1. Dr. Archara Supavavej (CRA)
    2. Dr. Kitwadee Saksornchai (CU)
    3. Dr. Kampanart Nimpoonsri (SI)
    4. Asst. Prof. Thitiya (Sirisinha) Dejthevaporn (Rama)

    Moderator:
    Assoc. Prof. Suebwong Chuthapisith (SI)