Breast cancer timeline: charting three decades of success

Although tumours in breast tissue have been observed in patients since ancient times, it wasn’t until the 1750s that scientists began to realise that cancer was a localised disease, and therefore could be surgically removed.

These theories led John Hopkins Hospital professor of surgery William Halsted to begin performing radical mastectomies. In these early surgeries, the whole breast was removed, as well as underlying chest muscle; later on, a patient’s collarbone was divided and the supraclavicular lymph nodes were also removed in the procedure.

Halsted found that local recurrence in the 50 patients he treated with this invasive procedure in the first 12 years fell from the 56% European average to 6%. However, there was little evidence of improvement in patient’s overall survival (OS). Despite this, radical mastectomies became the standard of care well into the 1900s.

Following the invention of the X-ray by Wilhelm Conrad Röentgen in 1896, radiation-based approaches quickly became used in diagnosis and treatment of various cancers. By the 1930s radiotherapy became used as an alternative to invasive radical mastectomy procedures, which were becoming increasingly controversial due to the associated disfigurement of patients and the inducing of sarcomas.

Over the next century, radiotherapy became significantly more targeted, effective and sensitive, and it remains one component of breast cancer therapy today.

First conceived during the Second World War as military uses of sulphur mustards were observed to have an impact on the bone marrow and lymph nodes of soldiers, the use of chemical-based therapies began to emerge as a possible treatment option for cancer in the 1950s and 1960s.

The primary way chemotherapy was used in breast cancer was in combination with surgery or radiotherapy treatments to add to the efficacy of their anti-tumour effects – so adjuvant chemotherapy became a staple in breast cancer treatment.

In the 1970s, chemotherapy’s usefulness to treat breast cancer on its own emerged. The first to be approved by the FDA was Pfizer’s doxorubicin, known as Adriamycin, in 1974. This drug is still used in breast cancer treatment today, despite its unpleasant side effects, which, combined with its red colour, has earned doxorubicin the nickname ‘Red Devil’.

Since the 19^th century, scientists had been aware of the hormonal basis of breast cancer, however, it took until 1977 for the FDA to approve the first anti-oestrogen drug, AstraZeneca’s Nolvadex (tamoxifen).

AstraZeneca had first synthesised it as a contraceptive in 1962, but later found it to be effective in oestrogen receptor-positive (ER+) tumours. Today it is still the gold-standard of treatment in ER+ tumours.

Since its initial approval, tamoxifen has been approved in further breast cancer indications, as studies revealed it was effective as adjuvant, post-surgery therapy and for preventative use in those at a high risk.

University of Pittsburgh professor of surgery Dr Bernard Fischer called for better clinical evaluation of treatment options through the use of randomised clinical trials.

He performed a study, in which he compared a radical mastectomy with a less invasive lumpectomy – known as breast-conserving surgery, as only a portion of the breast is removed – combined with radiotherapy. The two surgical techniques had the same survival rates, causing lumpectomy to begin to be used as standard treatment.

Following the discovery of epidermal growth factor receptor (EGFR) as potential breast cancer target in 1974, scientists cloned the HER2 gene, which is a member of the EGFR family, and demonstrated it was over-expressed in breast cancer patients.

Genentech demonstrated that a monoclonal antibody, named Herceptin (trastuzumab), which targeted the HER2 oncogene could specifically inhibit the growth of HER2-positive (HER2+) breast cancer cells. The company received fast track FDA approval for the immunotherapy in 1998.

In 1994, breakthroughs were made in understanding the genetic underpinning of breast cancer when researchers identified two breast-cancer associated genes, BRCA1 and BRCA2, and that carriers of mutations in these genes had a significantly higher – between 40% and 80% - risk of developing breast cancer.

As a result, since the mid-1990s, BRCA genetic testing has become crucial to identifying risk profile in breast cancer and ensuring early diagnosis, which key in this type of cancer.

Following this, in the early 2000s, studies began to investigate the possibility of a preventative mastectomy for BRCA positive patients. Although more invasive than lumpectomies, these mastectomies can help to preserve breast skin and allow for more natural chest appearance post-procedure than the 1880s versions.

Herceptin is an example of a monoclonal antibody-based immunotherapy in breast cancer, however, in contrast to other cancers, researchers have largely struggled to use drugs to trigger immune-based responses from breast cancer tumours.

An important breakthrough in immunotherapy outside of patients with HR+ or HER2+ tumours, which Herceptin and Tykerb can target, is the FDA’s March 2019 approval of Roche’s Tecentriq (atezolizumab) for patients triple-negative, metastatic breast cancer whose tumours express programmed death-ligand 1.

Triple-negative breast cancer tumours do not express receptors for oestrogen, progesterone or HER2, meaning the existing therapies are largely ineffectual in this patients and there is a serious unmet need.

Although it is rare, breast cancer can occur in men as they also have small amounts of breast tissue; a fact that remains relatively unknown.

Unfortunately, the small size of this patient group means that men are largely excluded from screening programmes and also creates serious challenges in conducting clinical trials. Consequently, there are limited options specifically for men and instead they are prescribed off-label drugs studied in women.

In 2019, Pfizer’s first-in-class drug Ibrance (palbociclib), which has been approved since 2015, was also sanctioned specifically for men, following the FDA approval of a label expansion based upon real-world evidence. However, more innovation is needed as Ibrance is only effective in ER+ and HER2+ breast cancer tumours.