Is it time to establish breast cancer as a smoking-related cancer?

Written by professor Inger Torhild Gram at the Department of Community Medicine.


We think it is time for public health agencies to review the data on smoking and breast cancer and reconsider whether the available evidence is sufficient to establish smoking as a cause of breast cancer. The results of our study, together with those from other recent cohort studies, support the notion that breast cancer is a smoking-related cancer.

Illustration photo:

Inger Torhild Gram Foto: privat

Smoking was established as a cause of lung cancer in the late 1950s. It then took another 50 years to establish that colorectal cancer was also a smoking-related cancer. However, as of 2018, a causal relationship between smoking and breast cancer had not yet been established. It may seem strange that it is taking so long to prove that smoking is a cause of all three of the most common cancers globally. Breast and lung cancer each account for 2.09 million cases annually and colorectal cancer for 1.8 million.

Data from 50 countries show that smoking is spreading from high-income countries to low- and middle-income countries. One consequence of this is that smoking among women and girls is predicted to double between 2005 and 2025.

Before smoking can be established as a cause of breast cancer, the association between smoking and breast cancer must first be shown in different populations. In our study, recently published in the International Journal of Epidemiology, we investigated whether the smoking-related increase in breast cancer was similar across five ethnic groups in the United States: African Americans, Native Hawaiians, Japanese Americans, Latinas and White Americans.

We followed more than 70,000 postmenopausal women who were enrolled in the Multiethnic Cohort study in 1993. The women completed a questionnaire and reported whether they had smoked at least 20 packs of cigarettes in their lifetime, the number of years they smoked cigarettes, the average number of cigarettes smoked per day during the period when they smoked, and the number of years since they quit smoking. We calculated age at smoking initiation and, for parous smokers, the years of smoking before their first childbirth. We adjusted our analyses by including known breast cancer risk factors (age, family history of breast cancer, education, body mass index, age at menarche, age at first childbirth, number of children, age at and type of menopause, post-menopausal hormone therapy and alcohol consumption) as covariates.

Overall, 4230 of the women were diagnosed with breast cancer during the following 17 years. We made four important findings from our study:

  • We found that if women smoked before giving birth to their first child, their risk of developing breast cancer later in life increased. This higher risk was confined to parous women who had started smoking more than 5 years before the birth of their first child.
  • We found that the magnitude of this higher breast cancer risk was consistent across African Americans, Native Hawaiians, Japanese Americans and White Americans.
  • We did not observe any association for Latinas, of whom only a small proportion had started to smoke before having their first child.
  • We found that a higher risk of smoking-related breast cancer seemed to be present, and of a similar magnitude, for both oestrogen and progestorone hormone receptor tumours.

One reason that recent cohort studies find a consistent association between smoking and breast cancer is that more women than in previous generations now initiate smoking during their teens. In a study of more than 300,000 Norwegian women, we found that the mean age at smoking initiation had lowered and that the proportion of women who started to smoke before their first childbirth had increased steadily, from 62% for those born before 1946 to 94% for those born after 1955. Fortunately, most women who smoke today report that they will stop smoking when they fall pregnant and have a child. However, teenagers and adolescent women need to be made aware that their risk of breast cancer is closely associated with the number of years they smoke before having their first child. Breast cancer is such a common disease that even a small increase in risk results in many new cases. As smoking, alcohol consumption and being overweight after 50 years of age are all avoidable risk factors, breast cancer prevention is, to some extent, possible.

There are more than 70 established carcinogens in cigarette smoke and more than 20 substances that induce mammary cancers in rodents. These compounds are also found in human breast tissue.

More than 40 years ago, scientists suggested there was biological plausibility for an association between cigarette smoking and breast cancer. They had identified nicotine, one of the major constituents of tobacco smoke, and its major metabolite cotinine in the breast fluid of non-lactating women who smoked. There are more than 70 established carcinogens in cigarette smoke and more than 20 substances that induce mammary cancers in rodents. These compounds are also found in human breast tissue. In 1982, Russo et al hypothesised that mammary tissue is more susceptible to carcinogenic exposures between menarche and the last trimester of the first pregnancy, when breast cells become fully differentiated. Our results support this hypothesis.

The article was first published at the blog for International Journal of Epidemiology January 29 2019.

About the author:

Inger Torhild Gram is a professor of preventive medicine in the Faculty of Health Sciences, Institute of Community Medicine at UiT the Arctic University of Norway, and a Visiting Professor in the Population Sciences in the Pacific, Epidemiology Program at the University of Hawaii Cancer Center.

Read more:

Gram IT, Park SY, Maskarinec G, et al. Smoking and breast cancer risk by race/ethnicity and oestrogen and progesterone receptor status: the Multiethnic Cohort (MEC) study. Int J Epidemiol 2019; Jan 18. doi: 10.1093/ije/dyy290.

Rituximab to be used with caution

By Emilio Besada, research fellow at the Bone and joint research group, Institute of Clinical Medicine, University of Tromsø

Rituximab, photo by NIAID

Photo by NIAID

Rituximab (MabThera®) has been used for over a decade to treat blood cells cancer and autoimmune diseases. Experience shows that Rituximab is a very effective and a “remarkably safe” drug. But in theory, Rituximab could increase the risk for infections since it turns off a part of the body’s defence (aka the immune system) against germs by killing B cells from the blood circulation.

Our clinical experience at the University of Tromsø in Norway agrees with the theory: long-term use of Rituximab in patients with Granulomatosis with polyangiitis or GPA increases the risk for severe infections

Revising our judgement about Rituximab

Early in the spring 2011, two patients with GPA, who were doing “remarkably” well with Rituximab, were hospitalized at the intensive care unit for severe pneumonia. By the end of 2011, other patients with GPA on Rituximab had infections. As we reviewed the patients’ medical files, we (re)discovered that some patients developed very low levels of antibodies while receiving Rituximab.

What is going on? B cells produce antibodies. Rituximab kills B cells and its prolonged use results in very low levels of antibodies. Antibodies neutralize and help destroy germs and very low levels of antibodies increase the risk for infections.

Improving patients’ outcome from death to remission

GPA is a severe form of vasculitis, formerly known as Wegener’s granulomatosis. GPA injures blood vessels walls leading to damage. It commonly affects the sinuses, lungs and kidneys, but it can affect almost all organs. It is a fatal disease if left untreated since half of the patients would die during the 6 months following diagnosis.

Conventional treatment with steroids (prednisolone/prednisone), drugs used in transplantation medicine (aka immunosuppressive drugs) and chemotherapy (cyclophosphamide) does not cure the disease, but prevents death and relapses in most patients. Patients feel better under continuous conventional treatment; however they seldom feel good since conventional treatment can also damage organ. Continuous use of high dose of steroids gives weight gain, mood disorders, osteoporosis, diabetes, high blood pressure, cataract and an increased risk for infections. Chemotherapy and immunosuppressive dugs increase the risk for infections and cancers.

On the other hand, Rituximab has slowly revolutionized treatment of patients with GPA. Compared to conventional treatment, Rituximab does not have the same risk for either cancer or infection and patients are able to stop steroids sooner. But since 2011, our expectations regarding Rituximab have become more reasonable.

Learning from experience

In our study, long-term use of Rituximab controlled the disease activity and decreased the risk to relapse by more than 80%. Patients were able to stop their immunosuppressive drugs and to either reduce or stop steroids preventing organ damage due to conventional treatment. In other words, patients got their life back while on Rituximab.

Unexpectedly, a third of the patients had to stop Rituximab after 4 years of treatment mainly due to low levels of antibodies and infections.

But the most important finding is that only a distinctive group of patients develops infections while using Rituximab. Patients at risk for infections are over the age of 60; they have a reduced kidney function and had received a lot of chemotherapy.

Is Rituximab a Faustian choice?

Rituximab works very well in patients with GPA and patients on Rituximab should not be afraid to use it. But patients are not equal and some will develop low levels of antibodies and infections during long-term Rituximab use. Therefore we need to adapt the treatment dose and duration according to each patient. The treatment goals are equal for all patients: to control the disease, to limit organ damage and infections risks. There is no Faustian choice: Rituximab achieves most of these goals, when used with caution.

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