Sita and Geeta and a tale of two tumors.

Mrs Sita (58 yrs) and Mrs Geeta (60 yrs) felt a lump in their breast. Both lived in the same city and immediately consulted a doctor (gynaecologist) who performed diagnostic mammogram and requested an ultrasound. The doctor who did ultrasound (radiologist) gave a bad news. He suspected them to have breast cancers. Sita and Geeta had the shock of their life. None of them had any close relatives with breast cancer. Both the patients were referred to the leading cancer doctor (oncologist) in the city. The oncologist got them biopsied. During biopsy, a small piece of breast tumor was taken and sent to a doctor (histopathologist) who examined thin sections of the tumor piece under a microscope. She gave the patients their reports which said ER+Her2- breast cancer. What the report meant was, their cancers were caused by increased amounts of estrogen receptor (ER) in their breast cells. Estrogen (E) is a hormone which is secreted in women and one of its function is to cause multiplication of breast cells. Normally, it enters breast cells and combines with estrogen receptors (ER). This binding of E-ER is important for the complex to enter nucleus of the breast cell, from where they cause the cell to divide into two daughter cells which leads to growth. Unfortunately, in both patients, their breast cells were producing much more amounts of estrogen receptors (ER) than normal. This led to excessive growth of breast cells leading to tumor formation. The ER+Her2- report also indicated that another receptor called as Her2 was produced in normal quantity.

The oncologist saw the report and gave a sigh of relief. While cancer is bad news, but relatively speaking, having ER+Her2- breast cancer was a good news, as some other types of breast cancers were even more challenging. The cancer was still local and the oncologist planned to manage it by giving hormone therapies after surgery. The oncologist referred both Sita and Geeta to a surgeon who removed most of the tumor and gave it again to the histopathologist. The histopthologist watched the tumor slices under the microscope and reported that “while most of the cancer cells are removed with the tumor lump, she could still see some cancer cells lingering in the lymph nodes”. This suggested that some cancer cells might have left the big tumor lump to other parts of the body. If that was true, these cells would eventually grow and make new tumors in other parts of the body in the time to come. In order to avoid that situation, the oncologist decided to suppress those escapee cells by giving “hormone therapy”. Oncologist already knew that the breast cells are growing because estrogen were able to bind to excessive amounts of ER. Thus she decided to give a drug called Tamoxifen which would bind to ER and would not let estrogen bind to ER. Tamoxifen came as pills to be taken once a day. Both Sita and Geeta went back to their original life styles with few changes. Oncologist asked Sita and Geeta to keep checking back with him on schedule to see if the cancer was creeping back. While Sita kept with that schedule without much change for next four years, it was Geeta who came back to the oncologist within a year with complaint of a small bulge near the area where she had the first tumor. Clearly the treatment didn’t work for her.

Over a period, Sita and Geeta had bonded while coming to the clinic and often they used to exchange notes. Geeta had the obvious question “how is it that Sita and I have the same cancer but her tumor never came back, but mine did”. Oncologist wasn’t surprised. Oncologist did consult Geeta that all cancer tumors are not the same, even when they happen at the same site or organ of the body. Since the site of recurrence was local, the oncologist gave her Anastrozole which is a drug that reduced production of estrogen. However, Geeta did not respond to this drug too and her recurred tumor grew more. Geeta was baffled at this enormous difference in the story of Sita and herself.

Oncologist consulted Geeta and talked about precision medicine. Its often referred as personalized medicine, meaning everyone’s cancer need a tailormade treatment, very specific to the patient’s tumor molecular biology. The oncologist asked Geeta to get a test done which was called Next Generation Sequencing (NGS) at a molecular testing laboratory. Geeta collected her biopsy tissue blocks from her histopathologist and went across the city to this another lab which did molecular testing. She met yet another doctor called “molecular pathologist”. Molecular pathologist gave her a broad smile and examined her tissue blocks before accepting. He also said that she should expect the report in next twelve days. “That is an unusually long time for a test”, Geeta said almost in protest, “and you are charging me a lot more than other tests that I have gotten done till now, can you please tell me why is that so”? The molecular pathologist consulted her “cancer is essentially a disease of molecular signaling. In each cell of our body, there are elaborate mechanisms which regulate the multiplication and growth of cells. Sometimes these mechanisms go haywire and the cell looses its control over growth which leads to continuous multiplication and tumor formation. In yours and Sita’s cases, the cancers did start because there was excessive production of estrogen receptor. So the oncologist prescribed you a medication that reduced production of estrogen. In the absence of estrogen, estrogen receptors could not bind to estrogen and could not stimulate cells to grow. Thus in the first year, both yours and Sita’s tumors reduced in size. However, in your case, probably there were small number of cells where the cancer was also driven by an entirely different signaling pathway”. The molecular pathologist went on, “each cell has these signaling pathways like intricate network of water pipes, almost a jungle of water pipes. If you close taps on one pipe, water finds a way to percolate into other pipe from the network and it starts to flow again. Similarly, in your case when the oncologist closed E-ER signaling pathway by giving you Tamoxifen, probably the cancer has found a way through other signaling pathways such as PIK3CA-AKT-mTOR or MAPkinase”. He pulled out a diagram (fig 1) that showed the pathways known to be involved in ER+Her2- breast cancer cells.

Approximately 18% of endocrine-resistant HR+ breast cancers have mutations in the ligand binding domain of ESR1 gene (that codes for estrogen receptor). Such tumors respond poorly to therapies like Tamoxifen and Aromatase inhibitors. It is indicated that a combinations of Fulvestrant with CDK4/6 inhibitors would work better than Tamoxifen or Aromatase inhibitor monotherapy. Apart from ESR1, activating mutations in MAPkinase pathway (such as EGFR, KRAS), ERBB2, NF1 loss-of- function mutations are also detected frequently in endocrine therapy resistant hormone positive breast cancers. Mutation profile of ER+Her2- metastatic breast tumor may help know the signalling pathway causing resistance against hormone therapy and also may help choose the most effective therapy for the progressed disease.