Among Michelangelo's most famous sculptures are the 'Prisoners” that depict human forms awakening from their marble entrapment. The sculptor believed that his work simply released the hidden figures from the stone. Like Michelangelo’s prisoners, intelligently selected chemotherapy can free cancer patients from the life-threatening encumbrance of their disease. On June 25th I met with a 43-year-old breast cancer patient to remove fluid from her chest cavity by ultrasound-guided thoracentesis. She had traveled from Missouri for our EVA/PCD analysis, referred by one our triple negative breast cancer patients from Utah. The fluid provided ample cells for study.
Case Study: Stage 4 HER-2 Positive Breast Cancer
Having been found to be HER2 (human epidermal growth factor 2) positive we knew that she would be a good candidate for the monoclonal antibodies that target HER2, Trastuzumab (Herceptin) and Pertuzumab (Perjeta). Unfortunately, at the time of her recent diagnosis she had widely metastatic disease involving lung and bone all arising from an extremely large and angry appearing right breast mass.
Looking for the Right Drug Combination
Knowing we could target HER2 with Trastuzumab and Pertuzumab the question remained, what chemotherapy drug(s) should we add to the mix to get the best response? With so large a number of cancer cells isolated we could test many combinations. One of the most widely used treatments for HER2 (+) patients is Trastuzumab plus Pertuzumab combined with the chemotherapy drug Docetaxel from the CLEOPATRA study (Swain, SM NEJM 2015). It was my expectation that this would be the best combination. But it wasn’t, not at all. That distinction went to Vinorelbine a somewhat milder drug that is often used as a single agent in breast cancer.
Our Past Research with Vinorelbine
Years earlier, I had discovered highly favorable interactions between Vinorelbine and Trastuzumab in studies conducted upon our HER2 (+) breast cancer patients using EVA/PCD analyses (Nagourney, RA, San Antonio Breast Cancer Symposium {SABCS}, 1999). At the time of my 1999 presentation, I thought the rather striking Vinorelbine observation, and one of very real clinical importance, would be well received but our human tumor studies were largely ignored by the symposium attendees who were far more interested in results from UCLA that used a commercially purchased breast cancer cell line known as MCF-7 to study the more toxic combination of Trastuzumab plus Paclitaxel (Taxol). As a large number of prior studies had already reported this combination, the novelty was lost on me.
That MCF-7 breast cancer cell line was originally derived from a 69-year-old woman in Michigan with breast cancer. It has been maintained in the laboratories of researchers all over the world since 1973. The fact that results with MCF-7 have shown little relevance to clinical therapy over the years did not seem to detract from the SABCS symposium crowd’s enthusiasm for these rather unoriginal findings. Nonetheless MCF-7 is the favorite of university investigators, who use it to generate publications on their way to professorship and tenure, the lack of clinical utility notwithstanding. It is disappointing that clinically validated human tissue studies like ours have never gotten the recognition that these cell line studies like those in MCF-7 cells regularly receive.
Harvard Study Vindicates Our Research
Despite this, it appeared that someone was paying attention, as several years later; the group from Harvard’s Dana Farber in Boston reported a 68% objective response rate using exactly that same combination of Vinorelbine plus Trastuzumab (Burstein, HJ et al., J. Clin. Oncol, 2003). Beyond a vindication of our observation, this led to the wide use of Vinorelbine plus Trastuzumab as an effective yet less toxic alternative to Paclitaxel or Docetaxel combinations.
More Information from Her Test Results
An additional observation was the highly favorable result when the drug Everolimus that targets another cellular pathway known as MTOR was added to the mix.
Everolimus has been successfully used in breast cancer for years and it has been shown that Everolimus combined with Vinorelbine plus Trastuzumab is safe and highly effective in previously treated, HER2 (+) breast cancer (BOLERO 3 Trial O’Regan, R J Clin Oncol 2013).
Our laboratory results confirmed that Vinorelbine plus the HER2- antibodies combined with low dose Everolimus was the most active of all the combinations tested.
Had Anyone Tried This Four Drug Combo Before?
I scoured the literature for prior studies that had combined all these agents but found none. We knew the BOLERO-3 trial used Vinorelbine plus Trastuzumab and Everolimus and a different study had combined Everolimus with Trastuzumab plus Paclitaxel. The CLEOPATRA combined Pertuzumab, Trastuzumab, and Docetaxel; while a more recent study combined Vinorelbine with Pertuzumab and Trastuzumab. Interestingly, in these published series it was the Estrogen (ER) and Progesterone (PR) receptor negative patients that had the best outcome with Everolimus, with a 74.2% response rate in one study. Here was just such a HER-2 (+); ER & PR (-) patient beckoning for our help.
I was faced with a bit of a dilemma.
No one had ever actually given Vinorelbine plus Trastuzumab plus Pertuzumab plus Everolimus. We needed to crosswalk several trials into one therapy. Never one to walk away from a challenge, I crafted the schedule and started the patient on treatment. She opted to remain in California for her first course that was given on the first and eighth day of a three-week cycle. After two cycles, she returned for the third. She was so anxious to assess her response that I agreed to repeat her PET/CT scan less than two months after beginning treatment.
Her Results with This New Combo
When compared with the study of late-June, the results were stunning. Only two cycles later the "interval decrease in the size and intensity of FDG accumulation associated with multiple previously seen lesions is consistent with a complete or near-complete response to therapy”. The pleural effusion had resolved, the enormous breast mass had disappeared, her bone metastasis were gone, and all other sites of disease were virtually undetectable. With no hair loss, bone marrow damage or significant side effects beyond mild mouth sores from the Everolimus, she approaches a complete remission with a regimen that no other breast cancer patient has ever received. It was crafted specifically for her.
Knowing that Vinorelbine favorably interacts with HER2 targeted agents, and that Everolimus regulates cancer metabolism this combination proved uniquely effective, yet would never have otherwise been given.
Lessons Learned
What can we learn from this? First, we know that HER2 positive breast cancers are highly responsive and that the availability of antibodies directed against the HER2 pathway has revolutionized therapy. Second, we know that cancer chemotherapies like Docetaxel and Vinorelbine can be synergistic with HER2-guided treatments. Third, we know that Everolimus can enhance the efficacy of other forms of treatment. What we have learned however, is that the careful selection of all these active drugs, the substitution of one drug for another, and the intelligent combination of pathway inhibitors can provide unheard of activity with little or no toxicity.
Where our treatment departed from the norm was first in the selection of Vinorelbine over Docetaxel, second adding Everolimus, and finally using only ½ dose Everolimus on an intermittent schedule. Indeed, her second-opinion physician at the University in St Louis actively argued against Everolimus stating that the patient did not carry the activating mutation for this drug. Like her genomic brethren at other universities, this doctor was mindlessly following DNA road maps while failing to incorporate the functional role of the MTOR as fundamental driver of tumor cell survival, whether mutated or not. In fact, MTOR cross talks with many signaling networks, most specifically HER2. More importantly, Everolimus clearly offered benefit both in the laboratory and in the patient. With so brilliant a response, the patient's physicians in Missouri will be more likely to adhere to our regimen. It was the patient’s initial concern that her doctors would not do so that led to her crossing the continent repeatedly for the first three cycles. With the luxury of a near complete response we can forcefully argue for continued treatment. Like Michelangelo’s prisoners, we were able rescue this nice young patient from the lethal embrace of her tumor, liberating her from untold toxicity and hardship. We could not be more pleased with her good outcome and will follow her closely.
As always, I appreciate your thoughts and comments.
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